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The Gastrointestinal Circulation: Physiology and Pathophysiology

D. Neil Granger, Lena Holm, Peter Kvietys

10.1002/cphy.c150007

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



ABSTRACT

The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response. © 2015 American Physiological Society. Compr Physiol 5:1541‐1583, 2015.

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Figure 1. Figure 1. The vascular organization of the gastric mucosa. The inset depicts the microvascular transport of HCO3 − from the acid secreting portion of the gastric pit to the surface epithelial cells (alkaline tide). Adapted, with permission, from Gannon, Browning, O'Brien, and Rogers. Gastroenterology 86: 866‐875, 1984 (146).
Figure 2. Figure 2. The vascular organization of the small intestinal mucosa. VA, villus arteriole; VV, villus venule. The inset depicts the base to apex pO2 gradient in the villi. Modified, with permission, from Frasher and Wayland. Microvasc Res 4: 62‐76, 1972 (136).
Figure 3. Figure 3. Myogenic mechanism of intrinsic regulation of the microcirculation. T, vessel wall tension; P, transmural pressure; r, vessel radius. Modified, with permission, from Granger, Kvietys, Korthuis, and Premen. Comprehensive Physiology 1405‐1474, 2011 (166).
Figure 4. Figure 4. Metabolic mechanism of intrinsic regulation of the microcirculation. O2, oxygen; pO2, oxygen tension. Modified, with permission, from Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 (166).
Figure 5. Figure 5. Oxygen consumption is better maintained than blood flow in digestive organs when blood pressure is reduced. The recruitment (opening) of more perfused capillaries at low pressures minimizes the distance that oxygen must diffuse between blood and parenchymal cells, thereby facilitating O2 exchange and maintaining O2 consumption. Large dot represents baseline values. Adapted, with permission, from Kvietys and Granger. The splanchnic circulation. In: Gastrointestinal Anatomy and Physiology: The essentials. JF Reinus and D Simon, editors. John Wiley & Sons, pp. 149‐163, 2014 (288).
Figure 6. Figure 6. Upper panel. Relationship between oxygen uptake and oxygen delivery (blood flow) under normal conditions and during enhanced or depressed oxidative metabolism. Lower panel. Relationship between oxygen uptake and oxygen delivery (blood flow) under normal conditions and during increased or reduced capillary density. Modified, with permission, from Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 (166).
Figure 7. Figure 7. Relationship between capillary filtration coefficient and capillary pressure in the cat small intestine. Capillary pressure was altered by venous pressure elevation or arterial pressurereduction. The inverse correlation is believed to result from myogenic control of perfused capillary density. Adapted, with permission, From Granger and Barrowman, Gastroenterology 84(4):846‐68, 1983 (160) and Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 (166).
Figure 8. Figure 8. The effects of increasing intestinal demand by intra‐arterial infusion of dinitrophenol (DNP) or instillation of digested food in the lumen (fed) on the vascular response to acute venous hypertension. Adapted, with permission, From Granger and Norris. Am J Physiol Heart Circ Physiol 238: H836‐H843, 1980 (175).
Figure 9. Figure 9. Simplified representation of the extrinsic and intrinsic innervation of submucosal arterioles. PVG, prevertebral ganglion; DRG, dorsal root ganglion; LM, longitudinal muscle; CM, circular muscle; NE, norepinephrine; ACh, acetylcholine; CGRP, calcitonin gene‐related peptide; SP, substance P; VIP, vasoactive intestinal peptide; IPAN, intrinsic primary afferent neurons; EPAN, extrinsic primary afferent neurons. Vasodilator influences (blue nerve terminals): CGRP, VIP, ACh. Vasoconstrictor influences (red nerve terminals): NE, ATP. [Modified, with permission, from Holzer (218).]
Figure 10. Figure 10. Relationship between oxygen uptake and blood flow (oxygen delivery). The curves depicted represent a composite of those shown in Figure 6. Alterations in tissue oxidative metabolism shift the “normal” curve vertically, while alterations in perfused capillary density shift the curve horizontally. The dot represents blood flow and oxygen uptake under normal conditions and the lettered arrows represent the potential effects of vasoactive agents on oxygen uptake. Pathway A is taken by a vasodilator that increases oxidative metabolism; Pathway B is taken by a vasodilator that does not affect oxidative metabolism or perfused capillary density; Pathway C is taken by a vasodilator that decreases capillary density; Pathway D is taken by a vasodilator that decreases metabolism; Pathway E is taken by a vasoconstrictor that decreases metabolism; Pathway F is taken by a vasoconstrictor that decreases capillary density; Pathway G is taken by a vasoconstrictor that does not affect tissue metabolism or capillary density; Pathway H is taken by a vasoconstrictor that increases capillary density; Pathway I is taken by a vasoconstrictor that increases metabolism. Adapted, with permission, from Kvietys and Granger. Am J Physiol 243: G1‐G9, 1982 (289).
Figure 11. Figure 11. Blood flow changes in the gastrointestinal tract of conscious dogs at 30 and 90 min following ingestion of a meal. * denotes P ≤ 0.05. Modified, with permission, from Gallavan et al. Am J Physiol 238: H220‐H225, 1980 (144).
Figure 12. Figure 12. Intestinal blood flow response following luminal placement of different specific constituents of chyme. Modified, with permission, from Granger et al. (166).
Figure 13. Figure 13. Effects of immunoblockade of either vasoactive intestinal peptide (VIP), cholecystokinin (CCK), or substance P (SP) on intestinal hyperemic response to solubilized oleic acid. * denotes significant change from corresponding untreated group. Modified, with permission, from Rozsa and Jacobson. Am J Physiol 256: G476‐G481, 1989 (407).
Figure 14. Figure 14. Blood flow responses in two adjacent segments of small intestine when the arterial inflow (A1) of one segment is suddenly occluded. V denotes venous drainage from corresponding segment.
Figure 15. Figure 15. Influence of ischemic duration and severity (complete vs. partial occlusion) on mucosal injury, as reflected by an increased intestinal mucosal permeability to albumin. Data, with permission, from Parks et al. (365).
Figure 16. Figure 16. Biphasic response of hydraulic conductivity in mesenteric venules exposed to ischemia and reperfusion (I/R). Modified, with permission, from Victorino et al. Am J Physiol Heart Circ Physiol 295: H2164‐H2171, 2008 (503).
Figure 17. Figure 17. (Panel A) Time course of changes in hydraulic conductivity and leukocyte adherence in mesenteric venules exposed to ischemia and reperfusion (I/R). (Panel B) Effects of ICAM‐1 immunoblockade on the hydraulic conductivity and leukocyte adherence responses to I/R. Modified, with permission, from Victorino et al. Am J Physiol Heart Circ Physiol 295: H2164‐H2171, 2008 (503).
Figure 18. Figure 18. Schematic of proposed influence of the balance between reactive oxygen species (ROS) and nitric oxide (NO) on the inflammatory and thrombogenic status of intestinal postcapillary venules under control conditions (when NO production greatly exceeds ROS production) and following ischemia‐reperfusion (when ROS production greatly exceeds NO production). Under control conditions (left panel), the balance between NO and ROS favors an anti‐inflammatory phenotype because NO chemistry predominates. The excess NO yields an anti‐inflammatory, antithrombogenic phenotype through sustained inhibition (related to target‐specific nitrosation) of transcription factor activation, and cGMP‐mediated, transcription‐independent signaling. Following ischemia/reperfusion (right panel), the balance between NO and ROS is shifted toward the latter species, either as a result of a reduction in NO biosynthesis, inactivation of NO by O2 •−, or both. In this instance, the flux of O2 •− relative to NO increases such that ROS‐dependent mechanisms predominate and NO‐dependent mechanisms are rendered inactive. ROS (and possibly RNOS)‐mediated transcription‐dependent and independent processes then promote a proinflammatory, pro‐thrombogenic phenotype, the intensity of which not only depends on the relative fluxes of NO and O2 •− but also on the specific RNOS formed. O2 −, superoxide; H2O2, hydrogen peroxide; ONOO, peroxynitrite; N2O3, dinitrogen trioxide; cGMP, cyclic GMP. Modified, with permission, from Free Radic Biol Med 33: 1026‐1036, 2002 (466a).
Figure 19. Figure 19. Effects of glucagon immunoblockade on portal hypertension‐induced hyperemia in rat jejunum. Based on data, with permission, from Benoit et al. Am J Physiol 251: G674‐G677, 1986 (36).
Figure 20. Figure 20. Reduced intestinal vascular sensitivity to vasoconstrictors in rats with chronic portal hypertension (CPH). Panel A shows reduced vascular sensitivity to norepinephrine [Kiel et al., Am J Physiol 248: G192, 1985 (254)]. Panel B shows reduced vascular sensitivity to arginine vasopressin (AVP), as well as the altered sensitivity to AVP in control rats with glucagon levels matching those detected in CPH rats. * denotes P < 0.05. Adapted, with permission, from Mesh et al. Gastroenterology 100: 916‐921, 1991 (330).
Figure 21. Figure 21. Stimuli for the development of porto‐systemic collaterals (PSC) in chronic portal hypertension.
Figure 22. Figure 22. Relationship between portal vein pressure and portal venous inflow predicted for normal (lower line) and portal vein stenosed (upper line) rats. The effects of increasing only portal venous pressure (pathway A to B), portal vascular resistance (pathway A to C) or a combination of both (pathway A to D) on portal pressure are shown. Rpv is portal vascular resistance in mmHg/mL min. Adapted, with permission, from Benoit et al. Gastroenterology 89: 1092, 1985 (34).
Figure 23. Figure 23. Impaired endothelium‐dependent vasodilation in colonic arterioles of (A) patients with inflammatory bowel disease and (B) in mice with dextran sodium sulfate (DSS)‐induced colitis. Control colonic arterioles exhibit a brisk dilatory response to (A) acetylcholine and (B) bradykinin. Colonic inflammation is associated with a diminished capacity of the arterioles to dilate to the same agonists. Mice that genetically overexpress copper zinc superoxide dismutase (SOD TgN) are protected [relative to wild‐type (WT) mice] against the DSS‐colitis induced inhibition of endothelium‐dependent vasodilation. Data derived, with permission, from Hatoum et al., Gastroenterology 125: 58‐69, 2003 (196) (panel A) and Mori et al. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005 (337) (panel B).
Figure 24. Figure 24. Time course of changes in disease activity index (A), vascular permeability (B), adherent platelets (C), adherent leukocytes (D), angiogenic index (E), and histopathologic score (F) in mice placed on dextran sodium sulfate (DSS) in drinking water for 6 days. Data derived, with permission, from Mori et al. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005 (337) (panels A‐D) and Chidlow et al. Am J Pathol 169: 2014‐2030, 2006 (81) (panels E‐F).
Figure 25. Figure 25. Ingested or salivary‐derived nitrate (NO3 −) is converted to nitrite (NO2 −) in the mouth by bacterial nitrate reductase (BNR). Upon swallowing, the NO2 − is reduced by H+ in gastric juice to form nitrous acid (HNO2), which decomposes to NO and other nitrogen oxides (N2O3 and NO2). NO can induce vasodilation and stimulate mucus production, while the nitrogen oxides are bactericidal.
Figure 26. Figure 26. Relationship between oxygen uptake and blood flow (or oxygen delivery) under basal conditions and during stimulation of acid secretion (from ref. 373 and 375). A secretagogue that has no effect on gastric blood flow will follow pathway A. A secretagogue that increases blood flow will follow pathway B. An antisecretory agent that increases gastric blood flow will follow pathway C.
Figure 27. Figure 27. The acid sensing pathway leading to a neurogenic hyperemia and HCO3 − secretion in the duodenum. Acid entering the interstitium can activate TRPV1 receptors on capsaicin‐sensitive EPANs which release of CGRP from their nerve terminals. CGRP dilates arterioles via an NO pathway as well as enhancing mucus/HCO3 − secretion. In the right portion of the schematic is a proposed mechanism by which acid delivery to the interstitium can be accomplished via luminal CO2 with no alteration in epithelial permeability. CA, carbonic anhydrase; HNE, H+/Na+ exchanger; TRP, transient receptor potential; ASIC, acid‐sensing ion channel; EPAN, extrinsic primary afferent neurons; CGRP, calcitonin gene‐related peptide; PG, prosataglandin. [Modified, with permission, from Holzer (218).]


Figure 1. The vascular organization of the gastric mucosa. The inset depicts the microvascular transport of HCO3 − from the acid secreting portion of the gastric pit to the surface epithelial cells (alkaline tide). Adapted, with permission, from Gannon, Browning, O'Brien, and Rogers. Gastroenterology 86: 866‐875, 1984 (146).


Figure 2. The vascular organization of the small intestinal mucosa. VA, villus arteriole; VV, villus venule. The inset depicts the base to apex pO2 gradient in the villi. Modified, with permission, from Frasher and Wayland. Microvasc Res 4: 62‐76, 1972 (136).


Figure 3. Myogenic mechanism of intrinsic regulation of the microcirculation. T, vessel wall tension; P, transmural pressure; r, vessel radius. Modified, with permission, from Granger, Kvietys, Korthuis, and Premen. Comprehensive Physiology 1405‐1474, 2011 (166).


Figure 4. Metabolic mechanism of intrinsic regulation of the microcirculation. O2, oxygen; pO2, oxygen tension. Modified, with permission, from Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 (166).


Figure 5. Oxygen consumption is better maintained than blood flow in digestive organs when blood pressure is reduced. The recruitment (opening) of more perfused capillaries at low pressures minimizes the distance that oxygen must diffuse between blood and parenchymal cells, thereby facilitating O2 exchange and maintaining O2 consumption. Large dot represents baseline values. Adapted, with permission, from Kvietys and Granger. The splanchnic circulation. In: Gastrointestinal Anatomy and Physiology: The essentials. JF Reinus and D Simon, editors. John Wiley & Sons, pp. 149‐163, 2014 (288).


Figure 6. Upper panel. Relationship between oxygen uptake and oxygen delivery (blood flow) under normal conditions and during enhanced or depressed oxidative metabolism. Lower panel. Relationship between oxygen uptake and oxygen delivery (blood flow) under normal conditions and during increased or reduced capillary density. Modified, with permission, from Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 (166).


Figure 7. Relationship between capillary filtration coefficient and capillary pressure in the cat small intestine. Capillary pressure was altered by venous pressure elevation or arterial pressurereduction. The inverse correlation is believed to result from myogenic control of perfused capillary density. Adapted, with permission, From Granger and Barrowman, Gastroenterology 84(4):846‐68, 1983 (160) and Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 (166).


Figure 8. The effects of increasing intestinal demand by intra‐arterial infusion of dinitrophenol (DNP) or instillation of digested food in the lumen (fed) on the vascular response to acute venous hypertension. Adapted, with permission, From Granger and Norris. Am J Physiol Heart Circ Physiol 238: H836‐H843, 1980 (175).


Figure 9. Simplified representation of the extrinsic and intrinsic innervation of submucosal arterioles. PVG, prevertebral ganglion; DRG, dorsal root ganglion; LM, longitudinal muscle; CM, circular muscle; NE, norepinephrine; ACh, acetylcholine; CGRP, calcitonin gene‐related peptide; SP, substance P; VIP, vasoactive intestinal peptide; IPAN, intrinsic primary afferent neurons; EPAN, extrinsic primary afferent neurons. Vasodilator influences (blue nerve terminals): CGRP, VIP, ACh. Vasoconstrictor influences (red nerve terminals): NE, ATP. [Modified, with permission, from Holzer (218).]


Figure 10. Relationship between oxygen uptake and blood flow (oxygen delivery). The curves depicted represent a composite of those shown in Figure 6. Alterations in tissue oxidative metabolism shift the “normal” curve vertically, while alterations in perfused capillary density shift the curve horizontally. The dot represents blood flow and oxygen uptake under normal conditions and the lettered arrows represent the potential effects of vasoactive agents on oxygen uptake. Pathway A is taken by a vasodilator that increases oxidative metabolism; Pathway B is taken by a vasodilator that does not affect oxidative metabolism or perfused capillary density; Pathway C is taken by a vasodilator that decreases capillary density; Pathway D is taken by a vasodilator that decreases metabolism; Pathway E is taken by a vasoconstrictor that decreases metabolism; Pathway F is taken by a vasoconstrictor that decreases capillary density; Pathway G is taken by a vasoconstrictor that does not affect tissue metabolism or capillary density; Pathway H is taken by a vasoconstrictor that increases capillary density; Pathway I is taken by a vasoconstrictor that increases metabolism. Adapted, with permission, from Kvietys and Granger. Am J Physiol 243: G1‐G9, 1982 (289).


Figure 11. Blood flow changes in the gastrointestinal tract of conscious dogs at 30 and 90 min following ingestion of a meal. * denotes P ≤ 0.05. Modified, with permission, from Gallavan et al. Am J Physiol 238: H220‐H225, 1980 (144).


Figure 12. Intestinal blood flow response following luminal placement of different specific constituents of chyme. Modified, with permission, from Granger et al. (166).


Figure 13. Effects of immunoblockade of either vasoactive intestinal peptide (VIP), cholecystokinin (CCK), or substance P (SP) on intestinal hyperemic response to solubilized oleic acid. * denotes significant change from corresponding untreated group. Modified, with permission, from Rozsa and Jacobson. Am J Physiol 256: G476‐G481, 1989 (407).


Figure 14. Blood flow responses in two adjacent segments of small intestine when the arterial inflow (A1) of one segment is suddenly occluded. V denotes venous drainage from corresponding segment.


Figure 15. Influence of ischemic duration and severity (complete vs. partial occlusion) on mucosal injury, as reflected by an increased intestinal mucosal permeability to albumin. Data, with permission, from Parks et al. (365).


Figure 16. Biphasic response of hydraulic conductivity in mesenteric venules exposed to ischemia and reperfusion (I/R). Modified, with permission, from Victorino et al. Am J Physiol Heart Circ Physiol 295: H2164‐H2171, 2008 (503).


Figure 17. (Panel A) Time course of changes in hydraulic conductivity and leukocyte adherence in mesenteric venules exposed to ischemia and reperfusion (I/R). (Panel B) Effects of ICAM‐1 immunoblockade on the hydraulic conductivity and leukocyte adherence responses to I/R. Modified, with permission, from Victorino et al. Am J Physiol Heart Circ Physiol 295: H2164‐H2171, 2008 (503).


Figure 18. Schematic of proposed influence of the balance between reactive oxygen species (ROS) and nitric oxide (NO) on the inflammatory and thrombogenic status of intestinal postcapillary venules under control conditions (when NO production greatly exceeds ROS production) and following ischemia‐reperfusion (when ROS production greatly exceeds NO production). Under control conditions (left panel), the balance between NO and ROS favors an anti‐inflammatory phenotype because NO chemistry predominates. The excess NO yields an anti‐inflammatory, antithrombogenic phenotype through sustained inhibition (related to target‐specific nitrosation) of transcription factor activation, and cGMP‐mediated, transcription‐independent signaling. Following ischemia/reperfusion (right panel), the balance between NO and ROS is shifted toward the latter species, either as a result of a reduction in NO biosynthesis, inactivation of NO by O2 •−, or both. In this instance, the flux of O2 •− relative to NO increases such that ROS‐dependent mechanisms predominate and NO‐dependent mechanisms are rendered inactive. ROS (and possibly RNOS)‐mediated transcription‐dependent and independent processes then promote a proinflammatory, pro‐thrombogenic phenotype, the intensity of which not only depends on the relative fluxes of NO and O2 •− but also on the specific RNOS formed. O2 −, superoxide; H2O2, hydrogen peroxide; ONOO, peroxynitrite; N2O3, dinitrogen trioxide; cGMP, cyclic GMP. Modified, with permission, from Free Radic Biol Med 33: 1026‐1036, 2002 (466a).


Figure 19. Effects of glucagon immunoblockade on portal hypertension‐induced hyperemia in rat jejunum. Based on data, with permission, from Benoit et al. Am J Physiol 251: G674‐G677, 1986 (36).


Figure 20. Reduced intestinal vascular sensitivity to vasoconstrictors in rats with chronic portal hypertension (CPH). Panel A shows reduced vascular sensitivity to norepinephrine [Kiel et al., Am J Physiol 248: G192, 1985 (254)]. Panel B shows reduced vascular sensitivity to arginine vasopressin (AVP), as well as the altered sensitivity to AVP in control rats with glucagon levels matching those detected in CPH rats. * denotes P < 0.05. Adapted, with permission, from Mesh et al. Gastroenterology 100: 916‐921, 1991 (330).


Figure 21. Stimuli for the development of porto‐systemic collaterals (PSC) in chronic portal hypertension.


Figure 22. Relationship between portal vein pressure and portal venous inflow predicted for normal (lower line) and portal vein stenosed (upper line) rats. The effects of increasing only portal venous pressure (pathway A to B), portal vascular resistance (pathway A to C) or a combination of both (pathway A to D) on portal pressure are shown. Rpv is portal vascular resistance in mmHg/mL min. Adapted, with permission, from Benoit et al. Gastroenterology 89: 1092, 1985 (34).


Figure 23. Impaired endothelium‐dependent vasodilation in colonic arterioles of (A) patients with inflammatory bowel disease and (B) in mice with dextran sodium sulfate (DSS)‐induced colitis. Control colonic arterioles exhibit a brisk dilatory response to (A) acetylcholine and (B) bradykinin. Colonic inflammation is associated with a diminished capacity of the arterioles to dilate to the same agonists. Mice that genetically overexpress copper zinc superoxide dismutase (SOD TgN) are protected [relative to wild‐type (WT) mice] against the DSS‐colitis induced inhibition of endothelium‐dependent vasodilation. Data derived, with permission, from Hatoum et al., Gastroenterology 125: 58‐69, 2003 (196) (panel A) and Mori et al. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005 (337) (panel B).


Figure 24. Time course of changes in disease activity index (A), vascular permeability (B), adherent platelets (C), adherent leukocytes (D), angiogenic index (E), and histopathologic score (F) in mice placed on dextran sodium sulfate (DSS) in drinking water for 6 days. Data derived, with permission, from Mori et al. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005 (337) (panels A‐D) and Chidlow et al. Am J Pathol 169: 2014‐2030, 2006 (81) (panels E‐F).


Figure 25. Ingested or salivary‐derived nitrate (NO3 −) is converted to nitrite (NO2 −) in the mouth by bacterial nitrate reductase (BNR). Upon swallowing, the NO2 − is reduced by H+ in gastric juice to form nitrous acid (HNO2), which decomposes to NO and other nitrogen oxides (N2O3 and NO2). NO can induce vasodilation and stimulate mucus production, while the nitrogen oxides are bactericidal.


Figure 26. Relationship between oxygen uptake and blood flow (or oxygen delivery) under basal conditions and during stimulation of acid secretion (from ref. 373 and 375). A secretagogue that has no effect on gastric blood flow will follow pathway A. A secretagogue that increases blood flow will follow pathway B. An antisecretory agent that increases gastric blood flow will follow pathway C.


Figure 27. The acid sensing pathway leading to a neurogenic hyperemia and HCO3 − secretion in the duodenum. Acid entering the interstitium can activate TRPV1 receptors on capsaicin‐sensitive EPANs which release of CGRP from their nerve terminals. CGRP dilates arterioles via an NO pathway as well as enhancing mucus/HCO3 − secretion. In the right portion of the schematic is a proposed mechanism by which acid delivery to the interstitium can be accomplished via luminal CO2 with no alteration in epithelial permeability. CA, carbonic anhydrase; HNE, H+/Na+ exchanger; TRP, transient receptor potential; ASIC, acid‐sensing ion channel; EPAN, extrinsic primary afferent neurons; CGRP, calcitonin gene‐related peptide; PG, prosataglandin. [Modified, with permission, from Holzer (218).]
References
 1. Abdel‐Salam OM , Czimmer J , Debreceni A , Szolcsanyi J , Mozsik G . Gastric mucosal integrity: Gastric mucosal blood flow and microcirculation. An overview. J Physiol Paris 95: 105‐127, 2001.
 2. Ahren C , Haglund U . Mucosal lesions in the small intestine of the cat during low flow. Acta Physiol Scand 88: 541‐550, 1973.
 3. Aihara E , Hayashi M , Sasaki Y , Kobata A , Takeuchi K . Mechanisms underlying capsaicin‐stimulated secretion in the stomach: Comparison with mucosal acidification. J Pharmacol Exp Ther 315: 423‐432. 2005.
 4. Aihara E , Hayashi M , Sasaki Y , Takeuchi K . Gastric HCO3 − secretion induced by mucosal acidification: Different mechanisms depending on acid concentration. Inflammopharmacology 13: 179‐190, 2005.
 5. Aihara E , Sasaki Y , Ise F , Kita K , Nomura Y , Takeuchi K . Distinct mechanisms of acid‐induced HCO3 − secretion in normal and slightly permeable stomachs. Am J Physiol Gastrointest Liver Physiol 291: G464‐G471, 2006.
 6. Akiba Y , Ghayouri S , Takeuchi T , Mizumori M , Guth PH , Engel E , Swenson ER , Kaunitz JD . Carbonic anhydrases and mucosal vanilloid receptors help mediate the hyperemic response to luminal CO2 in rat duodenum. Gastroenterology 131: 142‐152, 2006.
 7. Akiba Y , Guth PH , Engel E , Nastaskin I , Kaunitz JD . Acid‐sensing pathways of rat duodenum. Am J Physiol 277: G268‐G274, 1999.
 8. Allen A , Flemstrom G , Garner A , Kivilaakso E . Gastroduodenal mucosal protection. Physiol Rev 73: 823‐857, 1993.
 9. Ammon HV , Thomas PJ , Phillips SF . Effects of oleic and ricinoleic acids on net jejunal water and electrolyte movement. Perfusion studies in man. J Clin Invest 53: 374‐379, 1974.
 10. Andoh A , Kimura T , Fukuda M , Araki Y , Fujiyama Y , Bamba T . Rapid intestinal ischaemia‐reperfusion injury is suppressed in genetically mast cell‐deficient Ws/Ws rats. Clin Exp Immunol 116: 90‐3, 1999.
 11. Anzueto L , Benoit JN , Granger DN . A rat model for studying the intestinal circulation. Am J Physiol 246: G56‐G61, 1984.
 12. Anzueto‐Hernandez L , Kvietys PR , Granger DN . Postprandial hemodynamics in the conscious rat. Am J Physiol 251: G117‐G123, 1986.
 13. Ardelean DS , Yin M , Jerkic M , Peter M , Ngan B , Kerbel RS , Foster FS , Letarte M . Anti‐VEGF therapy reduces intestinal inflammation in Endoglin heterozygous mice subjected to experimental colitis. Angiogenesis 17: 641‐59, 2014.
 14. Armstrong, R. B. and M. H. Laughlin . Exercise blood flow patterns within and among rat muscles after training. Am J Physiol 246(1 Pt 2): H59‐H68, 1984.
 15. Arranz CT , Balaszczuk AM , Costa MA , Eizayaga FX , Romay S , Monelli C , Lemberg A . Systemic baroreceptor alterations in prehepatic portal hypertensive conscious rats. Arch Physiol Biochem 103: 422‐6, 1995.
 16. Asaduzzaman M , Mihaescu A , Wang Y , Sato T , Thorlacius H . P‐selectin and P‐selectin glycoprotein ligand 1 mediate rolling of activated CD8+ T cells in inflamed colonic venules. J Investig Med 57: 765‐768, 2009.
 17. Ashton T , Young IS , Davison GW , et al. Exercise‐induced endotoxemia: The effect of ascorbic acid supplementation. Free Radic Biol Med 35: 284‐91, 2003.
 18. Atucha N , Shah V , Garcia‐Cardena G , Sessa W , Groszmann R . Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis. Gastroenterology 111: 1627‐1632, 1996.
 19. Auer J , Reeh PW , Fischer MJ . Acid‐induced CGRP release from the stomach does not depend on TRPV1 or ASIC3. Neurogastroenterol Motil 22: 680‐687, 2010.
 20. Aychek T , Vandoorne K , Brenner O , Jung S , Neeman M . Quantitative analysis of intravenously administered contrast media reveals changes in vascular barrier functions in a murine colitis model. Magn Reson Med 66: 235‐43, 2011.
 21. Babbs CF , Cregor MD , Badylak SF . Histochemical demonstration of endothelial superoxide and hydrogen peroxide generation in ischaemic and reoxygenated rat tissues. Cardiovasc Res 26: 593‐602, 1992.
 22.(D116) Babior BM . The activity of leukocyte NADPH oxidase: Regulation by p47PHOX cysteine and serine residues. Antioxid. Redox Signal 4: 35‐8, 2002.
 23. Baek EB , Kim SJ . Mechanisms of myogenic response: Ca(2+)‐dependent and ‐independent signaling. J Smooth Muscle Res 47: 55‐65, 2011.
 24. Bagi Z , Frangos JA , Yeh JC , White CR , Kaley G , Koller A . PECAM‐1 mediates NO‐dependent dilation of arterioles to high temporal gradients of shear stress. Arterioscler Thromb Vasc Biol 25: 1590‐5, 2005.
 25. Bahari HM , Ross IN , Turnberg LA . Demonstration of a pH gradient across the mucus layer on the surface of human gastric mucosa in vitro. Gut 23: 513‐516, 1982.
 26. Balligand JL , Feron O , Dessy C . eNOS activation by physical forces: From short‐term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89: 481‐534, 2009.
 27. Bandi JC , Fernández M , Bernadich C , De Lacy AM , García‐Pagán JC , Bosch J , Rodés J . Hyperkinetic circulation and decreased sensitivity to vasoconstrictors following portacaval shunt in the rat. Effects of chronic nitric oxide inhibition. J Hepatol 31: 719‐24, 1999.
 28. Batelli MG , Della Corte E , Stirpe F . Xanthine oxidase type d (dehydrogenase) in the intestine and other organs of the rate. Biochem J 126: 747‐749, 1972.
 29. Batterbee HD , Farrar GE , Spears RP . Responses to hypotension in conscious rats with chronic portal hypertension. Am J Physiol 259: G48‐G55, 1990.
 30. Becker F , Yi P , Al‐Kofahi M , Ganta VC , Morris J , Alexander JS . Lymphatic dysregulation in intestinal inflammation: New insights into inflammatory bowel disease pathomechanisms. Lymphology 47: 3‐27, 2014.
 31. Bennett CF , Kornbrust D , Henry S , Stecker K , Howard R , Cooper S , Dutson S , Hall W , Jacoby HI . An ICAM‐1 antisense oligonucleotide prevents and reverses dextran sulfate sodium‐induced colitis in mice. J Pharmacol Exp Ther 280: 988‐1000, 1997.
 32. Benoit JN , Barrowman JA , Harper SL , Kvietys PR , Granger DN . Role of humoral factors in the intestinal hyperemia associated with chronic portal hypertension. Am J Physiol 247: G486‐G93, 1984.
 33. Benoit JN , Granger DN . Splanchnic hemodynamics in chronic portal hypertension. Semin Liver Dis 6: 287, 1986.
 34. Benoit JN , Womack WA , Hernandez L , Granger DN . “Forward” and “backward” flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis. Gastroenterology 89: 1092, 1985.
 35. Benoit JN , Womack WA , Korthuis RJ , Wilborn WH , Granger DN . Chronic portal hypertension: Effects on gastrointestinal blood flow distribution. Am J Physiol 250: G535‐G539, 1986.
 36. Benoit JN , Zimmerman B , Premen AJ , Go VL , Granger DN . Role of glucagon in splanchnic hyperemia of chronic portal hypertension. Am J Physiol 251: G674‐G677, 1986.
 37. Bergeron R , Kjaer M , Simonsen L , et al. Splanchnic blood flow and hepatic glucose production in exercising humans: Role of renin‐angiotensin system. Am J Physiol Regul Integr Comp Physiol 281: R1854‐R1861, 2001.
 38. Bernhard Angermayr , Mercedes Fernandez , Marc Mejias , Jorge Gracia‐Sancho , Juan Carlos Garcia‐Pagan , Jaime Bosch . NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut 56: 560‐564, 2007.
 39. Biber B , Fara J , Lundgren O . A pharmacological study of intestinal vasodilator mechanisms in the cat. Acta Physiol Scand 90: 673‐683, 1974.
 40. Biber B , Lundgren O , Svanvik J . Studies on the intestinal vasodilation observed after mechanical stimulation of the mucosa of the gut. Acta Physiol Scand 82: 177‐190, 1971.
 41. Bjorne HH , Petersson J , Phillipson M , Weitzberg E , Holm L , Lundberg JO . Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Invest 113: 106‐114, 2004.
 42.D223. Blanchet L , Lebrec D . Changes in splanchnic blood flow in portal hypertensive rats. Eur J Clin Invest 12: 327‐330, 1982.
 43.D80. Bohlen HG . Integration of intestinal structure, function, and microvascular regulation. Microcirculation 5: 27‐37, 1998.
 44. Bohlen HG . Intestinal mucosal oxygenation influences absorptive hyperemia. Am J Physiol 239: H489‐H493, 1980.
 45. Bohlen HG . Intestinal tissue pO2 and microvascular responses during glucose exposure. Am J Physiol 238(2): H164‐H171, 1980.
 46. Bohlen HG . Na+‐induced intestinal interstitial hyperosmolality and vascular responses during absorptive hyperemia. Am J Physiol 242: H785, 1982.
 47. Bohlen HG . Mechanism of increased vessel wall nitric oxide concentrations during intestinal absorption. Am J Physiol 275: H542‐H550, 1998.
 48.P67 Bohlen HG , Lash JM . Intestinal absorption of sodium and nitric oxide‐dependent vasodilation interact to dominate resting vascular resistance. Circ Res 78: 231‐7, 1996.
 49. Bohlen HG , Nase GP . Dependence of intestinal arteriolar regulation on flow‐mediated nitric oxide formation. Am J Physiol Heart Circ Physiol 279: H2249‐H2258, 2000.
 50. Bohlen HG , Unthank JL . Rat intestinal lymph osmolarity during glucose and oleic acid absorption. Am J Physiol 257: G438, 1989.
 51. Bomzon A , Blendis LM . Vascular reactivity in experimental portal hypertension. Am J Physiol 252: G158‐G162, 1987.
 52. Bond JH , Prentiss RA , Levitt MD . The effects of feeding on blood flow to the stomach, small bowel, and colon of the conscious dog. J Lab Clin Med 93: 594‐599, 1979.
 53. Borgstrom B , Dahlquist A , Lundh G , Sjovall J . Studies of intestinal digestion and absorption in the human. J Clin Invest 36: 1521‐1536, 1958.
 54. Boros M , Ordögh B , Kaszaki J , Nagy S . The role of mast cell degranulation in ischaemia‐reperfusion‐induced mucosal injury in the small intestine. Ann Acad Med Singapore 28: 79‐84, 1999.
 55. Bosenberg AT , Brock‐Utne JG , Gaffin SL , Wells MT , Blake GT . Strenuous exercise causes systemic endotoxemia. J Appl Physiol 65: 106‐108, 1988.
 56. Bounous G . Acute necrosis of the intestinal mucosa. Gastroenterology 82: 1457‐1467, 1982.
 57. Bounous G , Brown RA , Mulder DS , Hampson LG , Gurd FN . Abolition of ‘tryptic enteritis’ in the shocked dog. Creation of an experimental model for study of human shock and its sequelae. Arch Surg 91: 371‐375, 1965.
 58. Bounous G , Hampson LG , Gurd FN . Cellular nucleotides in hemorrhagic shock: Relationship of intestinal metabolic changes to hemorrhagic enteritis and the barrier function of intestinal mucosa. Ann Surg 160: 650‐666, 1964.
 59. Bounous G , Menard D , De Medicis E. Role of pancreatic proteases in the pathogenesis of ischemic enteropathy. Gastroenterology 73: 102‐108, 1977.
 60. Brain SD , Grant AD . Vascular actions of calcitonin gene‐related peptide and adrenomedullin. Physiol Rev 84: 903‐934, 2004.
 61. Brodie TG , Cullis W , Halliburton W . The gaseous metabolism of the small intestine. II. The gaseous exchanges during the absorption of Witte's peptone. J Physiol Lond 40: 173‐189, 1910.
 62. Brown JF , Hanson PJ , Whittle BJ . Nitric oxide donors increase mucus gel thickness in rat stomach. Eur J Pharmacol 223: 103‐104, 1992.
 63. Bryan NS , Bian K , Murad F . Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci (Landmark Ed) 14: 1‐18, 2009.
 64. Bulkley GB , Kvietys PR , Parks DA , Perry MA , Granger DN . Relationship of blood flow and oxygenation to ischemic injury in the canine small intestine. Gastroenterology 89: 852, 1985.
 65. Bulkley GB , Womack WA , Downey JM , Kvietys PR , Granger DN . Characterization of segmental collateral blood flow in the small intestine. Am J Physiol 249: G228‐G235, 1985.
 66. Burns RC , Rivera‐Nieves J , Moskaluk CA , Matsumoto S , Cominelli F , Ley K . Antibody blockade of ICAM‐1 and VCAM‐1 ameliorates inflammation in the SAMP‐1/Yit adoptive transfer model of Crohn's disease in mice. Gastroenterology 121: 1428‐36, 2001.
 67. Camus G , Nys M , Poortmans JR , et al. Endotoxaemia, production of tumour necrosis factor alpha and polymorphonuclear neutrophil activation following strenuous exercise in humans. Eur J Appl Physiol Occup Physiol 79: 62‐8, 1998.
 68. Carden DL , Granger DN . Pathophysiology of ischaemia‐reperfusion injury. J Pathol 190: 255, 2000.
 69. Carlson BE , Arciero JC , Secomb TW . Theoretical model of blood flow autoregulation: Roles of myogenic, shear‐dependent, and metabolic responses. Am J Physiol Heart Circ Physiol 295: H1572‐H1579, 2008.
 70. Carter PR , McElhatten RM , Zhang S , Wright WS , Harris NR . Thromboxane‐prostanoid receptor expression and antagonism in dextran‐sodium sulfate‐induced colitis. Inflamm Res 60: 87‐92, 2011.
 71. Carty E , Nickols C , Feakins RM , Rampton DS . Thromboxane synthase immunohistochemistry in inflammatory bowel disease. J Clin Pathol 55: 367‐370, 2002.
 72. Carty E , Rampton DS , Schneider H , Rutgeerts P , Wright JP . Lack of efficacy of ridogrel, a thromboxane synthase inhibitor, in a placebo‐controlled, double‐blind, multi‐centre clinical trial in active Crohn's disease. Aliment Pharmacol Ther 15: 1323‐1329, 2001.
 73. Casadevall M , Pique J , Cirera I , Goldin E , Elizalde I , Panes J , Martinez‐Cuesta M , Bosch J , Rodes J . Increased blood hemoglobin attenuates splanchnic vasodilation in portal‐hypertensive rats by nitric oxide inactivation. Gastroenterology 110: 1156‐1165, 1996.
 74. Casley‐Smith J , Gannon BJ . Intestinal microcirculation: Spatial organization and fine structure. In: Shepherd AP , Granger DN , editors. Physiology of the Intestinal Circulation. New York: Raven Press, 1984, pp. 9‐31.
 75. Caterina MJ , Schumacher MA , Tominaga M , Rosen TA , Levine JD , Julius D . The capsaicin receptor: A heat‐activated ion channel in the pain pathway. Nature 389: 816‐824, 1997.
 76. Chan SL , Fiscus RR . Vasorelaxations induced by calcitonin gene‐related peptide, vasoactive intestinal peptide, and acetylcholine in aortic rings of endothelial and inducible nitric oxide synthase‐knockout mice. J Cardiovasc Pharmacol 41: 434‐443, 2003.
 77. Chang M , Asaigh T , Kistler EB , Schmid‐Schönbein GW . Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine. PLoS One 7: e40087, 2012.
 78. Cheung LY , Moody FG , Larson K , Lowry SF . Oxygen consumption during cimetidine and prostaglandin E2 inhibition of acid secretion. Am J Physiol 234: E445‐E450, 1978.
 79. Chidlow JH Jr , Glawe JD , Pattillo CB , Pardue S , Zhang S , Kevil CG . VEGF164 isoform specific regulation of T‐cell‐dependent experimental colitis in mice. Inflamm Bowel Dis 17: 1501‐1512, 2011.
 80. Chidlow JH Jr , Greer JJ , Anthoni C , Bernatchez P , Fernandez‐Hernando C , Bruce M , Abdelbaqi M , Shukla D , Granger DN , Sessa WC , Kevil CG . Endothelial caveolin‐1 regulates pathologic angiogenesis in a mouse model of colitis. Gastroenterology 136: 575‐584, 2009.
 81. Chidlow JH Jr , Langston W , Greer JJ , Ostanin D , Abdelbaqi M , Houghton J , Senthilkumar A , Shukla D , Mazar AP , Grisham MB , Kevil CG . Differential angiogenic regulation of experimental colitis. Am J Pathol 169: 2014‐2030, 2006.
 82. Chiu CJ , McArdle AH , Brown R , Scott HJ , Gurd FN . Intestinal mucosal lesion in low‐flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 101: 478, 1970.
 83. Cho KJ , Schmidt RW , Lenz J Effects of experimental embolization of superior mesenteric artery branch on the intestine. Invest Radiol 14: 207‐212, 1979.
 84. Chojkier M , Groszmann RJ . Measurement of portalsystemic shunting in the rat by using γ‐labeled microspheres. Am J Physiol 240: G371‐G375, 1981.
 85. Chou CC . Relationship between intestinal blood flow and motility. Annu Rev Physiol 44: 29‐42, 1982.
 86. Chou CC . Splanchnic and overall cardiovascular hemodynamics during eating and digestion. Fed Proc 42: 1658, 1983.
 87. Chou CC , Burns TD , Hsieh CP , Dabney JM . Mechanism of local vasodilation with hypertonic glucose in the jejunum. Surgery 71: 380‐387, 1972.
 88. Chou CC , Gallavan RH . Blood flow and intestinal motility. Fed Proc 41: 2090‐2095, 1982.
 89. Chou CC , Grassmick B . Motility and blood flow distribution within the wall of the gastrointestinal tract. Am J Physiol 235: H34‐H39, 1978.
 90. Chou CC , Hsieh CP , Burns TD , Dabney JM . Effects of lumen pH and osmolarity on duodenal blood flow and motility (Abstract). Gastroenterology 60: 648, 1971.
 91. Chou CC , Hsieh CP , Yu YM , Kvietys P , Yu LC , Pittman R , Dabney JM . Localization of mesenteric hyperemia during digestion in dogs. Am J Physiol 230: 583‐589, 1976.
 92. Chou CC , Kvietys P , Post J , Sit SP . Constituents of chyme responsible for postprandial intestinal hyperemia. Am J Physiol 235(6): H677‐H682, 1978.
 93. Chou CC , Nyhof RA , Kvietys PR , Sit SP , Gallavan RH, Jr . Regulation of jejunal blood flow and oxygenation during glucose and oleic acid absorption. Am J Physiol 249: G691‐G701, 1985.
 94. Chretien ML , Zhang M , Jackson MR , Kapus A , Langille BL . Mechano‐transduction by endothelial cells is locally generated, direction‐dependent, and ligand‐specific. J Cell Physiol 224: 352‐361, 2010.
 95. Christensen NJ , Galbo H . Sympathetic nervous activity during exercise. Annu Rev Physiol 45: 139‐153, 1983.
 96. Chu C , Lee F , Wang S , Lu R , Tsai Y , Lin H , Hou M , et al. Hyperdynamic circulation of cirrhotic rats with ascites: Role of endotoxin, tumour necrosis factor and nitric oxide. Clinical Science 93: 219‐225, 1997.
 97. Clausen JP . Effect of physical training on cardiovascular adjustments to exercise in man. Physiol Rev 57: 779‐815, 1977.
 98. Colgan SP , Taylor CT . Hypoxia: An alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7: 281‐287, 2010.
 99. Colle I , Geerts AM , van Steenkiste C , van Vlierberghe H . Hemodynamic changes in splanchnic blood vessels in portal hypertension. Anat Rec 292: 699‐713, 2008.
 100. Convertino VA , Keil LC , Greenleaf JE . Plasma volume, renin, and vasopressin responses to graded exercise after training. J Appl Physiol 54: 508‐514, 1983.
 101. Costa M , Furness JB . The origins, pathways and terminations of neurons with VIP‐like immunoreactivity in the guinea‐pig small intestine. Neuroscience 8: 665, 1983.
 102. Crissinger KD , Burney DL . Postprandial hemodynamics and oxygenation in developing piglet intestine. Am J Physiol 260: G951, 1991.
 103. Crissinger KD , Kvietys PR , Granger DN . Autoregulatory escape from norepinephrine infusion: Roles of adenosine and histamine. Am J Physiol 254: G560‐G565, 1988.
 104. Cromer WE , Ganta CV , Patel M , Traylor J , Kevil CG , Alexander JS , Mathis JM . VEGF‐A isoform modulation in a preclinical TNBS model of ulcerative colitis: Protective effects of a VEGF164b therapy. J Transl Med 11: 207, 2013.
 105. Cromer WE , Mathis JM , Granger DN , Chaitanya GV , Alexander JS . Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol 17: 578‐593, 2011.
 106. Cummings S , Groszmann RJ , Kaumann AJ . Hypersensitivity of mesenteric veins to 5‐hydroxytryptamine‐ and ketanserin‐induced reduction of portal pressure in portal hypertensive rats. Br J Pharmacol 89: 501, 1986.
 107. Cuzzocrea S , Mazzon E , Dugo L , Caputi AP , Aston K , Riley DP , Salvemini D . Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion. Br J Pharmacol 132: 19‐29, 2001.
 108. D'Alessio S , Correale C , Tacconi C , Gandelli A , Pietrogrande G , Vetrano S , Genua M , Arena V , Spinelli A , Peyrin‐Biroulet L , Fiocchi C , Danese S . VEGF‐C‐dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest 124: 3863‐78, 2014.
 109. D'Alessio S , Tacconi C , Fiocchi C , Danese S . Advances in therapeutic interventions targeting the vascular and lymphatic endothelium in inflammatory bowel disease. Curr Opin Gastroenterol 29: 608‐613, 2013.
 110. Danese S . Role of the vascular and lymphatic endothelium in the pathogenesis of inflammatory bowel disease: ‘Brothers in arms’. Gut 60: 998‐1008, 2011.
 111. Danese S , de la Motte C , Sturm A , Vogel JD , West GA , Strong SA , Katz JA , Fiocchi C . Platelets trigger a CD40‐dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 124: 1249‐1264, 2003.
 112. Davis MJ . Perspective: Physiological role(s) of the vascular myogenic response. Microcirculation 19: 99‐114, 2012.
 113. Davis MJ , Gore RW . Capillary pressures in rat intestinal muscle and mucosal villi during venous pressure elevation. Am J Physiol 249: H174‐H187, 1985.
 114. Deitch EA , Bridges W , Baker J , Ma JW , Ma L , Grisham MB , Granger DN , Specian RD , Berg R . Hemorrhagic shock‐induced bacterial translocation is reduced by xanthine oxidase inhibition or inactivation. Surgery 104: 191‐198, 1988.
 115. Deshmukh DR , Mirochnitchenko O , Ghole VS , Agnese D , Shah PC , Reddell M , Brolin RE , Inouye M . Intestinal ischemia and reperfusion injury in transgenic mice overexpressing copper‐zinc superoxide dismutase. Am J Physiol 273: C1130‐C1135, 1997.
 116. Di Giantomasso D , May CN , Bellomo R . Vital organ blood flow during hyperdynamic sepsis. Chest 124(3): 1053‐1059, 2003.
 117. Drummond HA , Grifoni SC , Jernigan NL . A new trick for an old dogma: ENaC proteins as mechanotransducers in vascular smooth muscle. Physiology (Bethesda) 23: 23‐31, 2008.
 118. Dykhuizen RS , Fraser A , McKenzie H , Golden M , Leifert C , Benjamin N . Helicobacter pylori is killed by nitrite under acidic conditions. Gut 42: 334‐337, 1998.
 119. Edelstone DI , Holzman IR . Oxygen consumption by the gastrointestinal tract and liver in conscious newborn lambs. Am J Physiol 240: G297, 1981.
 120. Edlich RF , Borner JW , Kuphal J , Wangensteen OH . Gastric blood flow. I. Its distribution during gastric distention. Am J Surg 120: 35‐37, 1970.
 121. Eguchi S , Tezuka S , Hobara N , Akiyama S , Kurosaki Y , Kawasaki H . Vanilloid receptors mediate adrenergic nerve‐ and CGRP‐containing nerve‐dependent vasodilation induced by nicotine in rat mesenteric resistance arteries. Br J Pharmacol 18(142): 1137‐1146, 2004.
 122. Eklund S , Fahrenkrug J , Jodal M , Lundgren O , Schaffalitzky de Muckadell OB , Sjoquist A . Vasoactive intestinal polypeptide, 5‐hydroxytryptamine, and reflex hyperemia in the small intestine of the cat. J Physiol Lond 302: 549‐557, 1980.
 123. Engerson TD , McElvey TG , Rhyne DB , Boggio EB , Snyder SJ , Jones HP . Conversion of xanthine dehydrogenase to xanthine oxidase in ischemic rat tissues. J Clin Invest 79: 1564‐1570, 1987.
 124. Esposito E , Mazzon E , Muià C , Meli R , Sessa E , Cuzzocrea S . Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF‐alpha. J Leukoc Biol 81: 1032‐1043, 2007.
 125. Fahrenkrug J , Haglund U , Jodal M , Lundgren O , Olbe L , Schaffalitzky de Muckadell OB . Nervous release of vasoactive intestinal polypeptide in the gastrointestinal tract of cats: Possible physiological implications. J Physiol Lond 284: 291‐305, 1978.
 126. Fara JW . Postprandial mesenteric hyperemia. In: Shepherd AP , Granger DN , editors. Physiology of the Intestinal Circulation, New York: Raven Press, 1984, pp. 99‐106.
 127. Fara JW , Rubinstein EH , Sonnenschein RR . Intestinal hormones in mesenteric vasodilation after intraduodenal agents. Am J Physiol 223: 1058‐1067, 1972.
 128. Fasth S , Hulten L . The effect of bradykinin on the consecutive vascular sections of the small and large intestine. Acta Chir Scand 139: 707‐715, 1973.
 129. Feinman R , Deitch EA , Watkins AC , Abungu B , Colorado I , Kannan KB , Sheth SU , Caputo FJ , Lu Q , Ramanathan M , Attan S , Badami CD , Doucet D , Barlos D , Bosch‐Marce M , Semenza GL , Xu DZ . HIF‐1 mediates pathogenic inflammatory responses to intestinal ischemia‐reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833‐G843, 2010.
 130. Fernandez M , Mejias M , Angermayr B , Garcia‐Pagan JC , Rodés J , Bosch J . Inhibition of VEGF receptor‐2 decreases the development of hyperdynamic splanchnic circulation and portal‐systemic collateral vessels in portal hypertensive rats. J Hepatol 243: 98‐103, 2005.
 131. Fernandez M , Vizzutti F , Garcia‐pagan JC , Rodés J , Bosch J . Anti‐VEGF receptor‐2 monoclonal antibody prevents portal‐systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 126: 886‐894, 2004.
 132. Fiddian‐Green RG , Pittenger G , Whitehouse WM, Jr . Back‐diffusion of CO2 and its influence on the intramural pH in gastric mucosa. J Surg Res 33(1): 39‐48, 1982.
 133. Fioramonti J , Bueno L . Relation between intestinal motility and mesenteric blood flow in the conscious dog. Am J Physiol 246: G108‐G113, 1984.
 134. Fleming I , Fisslthaler B , Dixit M , Busse R . Role of PECAM‐1 in the shear‐stress‐induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci 118: 4103‐4111, 2005.
 135. Folkow B , Lewis DH , Lundgren O , Mellander S , Wallentin I . The effect of graded vasoconstrictor fibre stimulation on the intestinal resistance and capacitance vessels. Acta Physiol Scand 61: 445‐457, 1964.
 136. Fordtran JS , Locklear TW . Ionic constituents and osmolality of gastric and small‐intestinal fluids after eating. Am J Dig Dis 11: 503‐521, 1966.
 137. Frasher WG, Jr , Wayland H . A repeating modular organization of the microcirculation of cat mesentery. Microvasc Res 4: 62‐76, 1972.
 138. Fronek K , Stahlgren LH . Systemic and regional hemodynamic changes during food intake and digestion in nonanesthetized dogs. Circ Res 23: 687‐692, 1968.
 139. Furchgott RF , Vanhoutte PM . Endothelium‐derived relaxing and contracting factors. FASEB J 3: 2007‐2018, 1989.
 140. Furchgott RF , Zawadzki JV . The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 27(288): 373‐376, 1980.
 141. Furness JB . Novel gut afferents: Intrinsic afferent neurons and intestinofugal neurons. Auton Neurosci 125: 81‐85, 2006.
 142. Furness JB , Stebbing MJ , Clerc N . Sensory neurons of the gastrointestinal tract. In: Yamada T , editor. Textbook of Gastroenterology (5th ed). John Wiley & Sons, 2011, pp. 34‐47.
 143. Gallavan RH, Jr , Chen MH , Joffe SN , Jacobson ED . Vasoactive intestinal polypeptide, cholecystokinin, glucagon, and bile‐oleate‐induced jejunal hyperemia. Am J Physiol 248: G208, 1985.
 144. Gallavan RH, Jr , Chou CC . Possible mechanisms for the initiation and maintenance of postprandial intestinal hyperemia. Am J Physiol 249: G301‐G308, 1985.
 145. Gallavan RH, Jr , Chou CC , Kvietys PR , Sit SP . Regional blood flow during digestion in the conscious dog. Am J Physiol 238: H220‐H225, 1980.
 146. Gallavan RH, Jr , Shaw C , Murphy RF , Buchanan KD , Joffe SN , Jacobson ED . Effects of micellar oleic acid on canine jejunal blood flow and neurotensin release. Am J Physiol 251: G649‐G655, 1986.
 147. Gannon B , Browning J , O'Brien P , Rogers P . Mucosal microvascular architecture of the fundus and body of human stomach. Gastroenterology 86: 866‐875, 1984.
 148. Ganta VC , Cromer W , Mills GL , Traylor J , Jennings M , Daley S , Clark B , Mathis JM , Bernas M , Boktor M , Jordan P , Witte M , Alexander JS . Angiopoietin‐2 in experimental colitis. Inflamm Bowel Dis 16: 1029‐1039, 2010.
 149. Garcia JG , Cruz MD , Rollan CM , Perez CP , Alonso AG . Superoxide dismutase (SOD) and neutrophil infiltration in intestinal ischaemia‐revascularization. Int Surg 80: 95‐97, 1995.
 150. Gati T , Guth PH . Mucosal lesions due to gastric distension in the rat. Am J Dig Dis 22: 1083‐1090, 1977.
 151. Gayle J , Jones SL , Argenzio RA , Blikslager AT . Neutrophils increase paracellular permeability of restituted ischemic‐injured porcine ileum. Surgery 132: 461‐470, 2002.
 152. Ge M , Gan X , Liu D , Zhang W , Gao W , Huang P , Hei Z . Time‐course analysis of counts and degranulation of mast cells during early intestinal ischemia‐reperfusion injury in mice. Mol Med Rep 8: 401‐406, 2013.
 153. Geboes K , Geboes KP , Maleux G . Vascular anatomy of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 15: 1‐14, 2001.
 154. Geleff S , Schoppmann SF , Oberhuber G . Increase in podoplanin‐expressing intestinal lymphatic vessels in inflammatory bowel disease. Virchows Arch 442: 231‐237, 2003.
 155. Gerber JG , Nies AS . The role of prostaglandins in histamine‐induced gastric vasodilation in the dog. J Pharmacol Exp Ther 213: 79‐84, 1980.
 156. Gerlach UA , Atanasov G , Wallenta L , Polenz D , Reutzel‐Selke A , Kloepfel M , Jurisch A , Marksteiner M , Loddenkemper C , Neuhaus P , Sawitzki B , Pascher A . Short‐term TNF‐alpha inhibition reduces short‐term and long‐term inflammatory changes post‐ischemia/reperfusion in rat intestinal transplantation. Transplantation 97: 732‐739, 2014.
 157. Gironella M , Mollà M , Salas A , Soriano A , Sans M , Closa D , Engel P , Salas A , Piqué JM , Panés J . The role of P‐selectin in experimental colitis as determined by antibody immunoblockade and genetically deficient mice. J Leukoc Biol 72: 56‐64, 2002.
 158. Glover LE , Colgan SP . Hypoxia and metabolic factors that influence inflammatory bowel disease pathogenesis. Gastroenterology 140: 1748‐1755, 2011.
 159. Goto A , Arimura Y , Shinomura Y , Imai K , Hinoda Y . Antisense therapy of MAdCAM‐1 for trinitrobenzenesulfonic acid‐induced murine colitis. Inflamm Bowel Dis 12: 758‐765, 2006.
 160. Granger DN . Role of xanthine oxidase and granulocytes in ischemia‐reperfusion injury. Am J Physiol 255: H1269‐H1275, 1988.
 161. Granger DN , Barrowman JA . Microcirculation of the alimentary tract I. Physiology of transcapillary fluid and solute exchange. Gastroenterology 84: 846‐868, 1983.
 162. Granger DN , Benoit JN , Suzuki M , Grisham MB . Leukocyte adherence to venular endothelium during ischemia‐reperfusion. Am J Physiol 257: G683‐G688, 1989.
 163. Granger DN , Granger HJ . Systems analysis of intestinal hemodynamics and oxygenation. Am J Physiol 245: G786‐G796, 1983.
 164. Granger DN , Kvietys PR . The splanchnic circulation: Intrinsic regulation. Annu Rev Physiol 43: 409‐418, 1981.
 165. Granger DN , Kvietys PR . Splanchnic circulation: Physiology and pathophysiology. American Gastroenterological Association‐Undergraduate Teaching Project (Unit #39), Cockeysville, MD: Milner‐Fenwick, Inc., 2000.
 166. Granger DN , Kvietys PR , Korthuis RJ , Premen AJ . Microcirculation of the intestinal mucosa. Compr Physiol 2011, Supplement 16: Handbook of Physiology, The Gastrointestinal System, Motility and Circulation 1405‐1474. First published in print 1989. doi: 10.1002/cphy.cp060139.
 167. Granger DN , Kvietys PR , Mailman D , Richardson PD . Intrinsic regulation of functional blood flow and water absorption in canine colon. J Physiol 307: 443‐451, 1980.
 168. Granger DN , Kvietys PR , Perry MA . Role of exchange vessels in the regulation of intestinal oxygenation. Am J Physiol 242: G570‐G574, 1982.
 169. Granger DN , McCord JM , Parks DA , Hollwarth ME . Xanthine oxidase inhibitors attenuate ischemia‐induced vascular permeability changes in the cat intestine. Gastroenterology 90: 80, 1986.
 170. Granger DN , Mortillaro NA , Perry MA , Kvietys PR . Autoregulation of intestinal capillary filtration rate. Am J Physiol 243: G475‐G483, 1982.
 171. Granger DN , Richardson PD , Kvietys PR , Mortillaro NA . Intestinal blood flow. Gastroenterology 78: 837‐63, 1980.
 172. Granger DN , Richardson PD , Taylor AE . Volumetric assessment of the capillary filtration coefficient in the cat small intestine. Pflugers Arch 381: 25‐33, 1979.
 173. Granger DN , Rutili G , McCord JM . Superoxide radicals in feline intestinal ischemia. Gastroenterology 81: 22‐29, 1981.
 174. Granger DN , Sennett M , McElearney P , Taylor AE . Effect of local arterial hypotension on cat intestinal capillary permeability. Gastroenterology 79: 474, 1980.
 175. Granger DN , Valleau JD , Parker RE , Lane RS , Taylor AE . Effects of adenosine on intestinal hemodynamics, oxygen delivery, and capillary fluid exchange. Am J Physiol 235: H707‐H719, 1978.
 176. Granger HJ , Norris CP . Intrinsic regulation of intestinal oxygenation in the anesthetized dog. Am J Physiol 238: H836‐H843, 1980.
 177. Granger HJ , Norris CP . Role of adenosine in local control of intestinal circulation in the dog. Circ Res 46: 764‐770, 1980.
 178. Granger HJ , Nyhof RA . Dynamics of intestinal oxygenation: Interactions between oxygen supply and uptake. Am J Physiol 243: G91‐G96, 1982.
 179. Greenway CV , Scott GD , Zink J . Sites of autoregulatory escape of blood flow in the mesenteric vascular bed. J Physiol 259: 1‐12, 1976.
 180. Grisham MB , Hernandez LA , Granger DN . Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251: G567‐G574, 1986.
 181. Grisham MB , Kevil CG , Harris NR , Granger DN . The role of the vasculature in chronic intestinal inflammation. In: Targan S , Shanahan F , Karp L , editors. Inflammatory Bowel Disease: Translating Basic Science into Clinical Practice. Oxford, UK: Blackwell Publishing, 2010, pp. 157‐169.
 182. Grogaard B , Parks DA , Granger DN , McCord JM , Forsberg JO . Effects of ischemia and oxygen radicals on mucosal albumin clearance in intestine. Am J Physiol 242: G448, 1982.
 183. Grootjans J , Lenaerts K , Derikx JP , Matthijsen RA , de Bruïne AP , van Bijnen AA , van Dam RM , Dejong CH , Buurman WA . Human intestinal ischemia‐reperfusion‐induced inflammation characterized: Experiences from a new translational model. Am J Pathol 176: 2283‐2291, 2010.
 184. Gu L , Yan CD , Du J , Tian SP , Li DS . Capsaicin‐sensitive afferent fibers and endogenous NO mediate the gastric acid secretion and gastric mucosal blood flow in intragastric distention in rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 19: 193‐196, 2003.
 185. Guth PH . Current concepts in gastric microcirculatory pathophysiology. Yale J Biol Med 65: 677‐688, 1992.
 186. Guth PH , Leung FW , Kauffman GL . Physiology of the gastric circulation. Compr Physiol 2011, Supplement 16: Handbook of Physiology, The Gastrointestinal System, Motility and Circulation 1371‐1404. First published in print 1989. doi: 10.1002/cphy.cp060138.
 187. Guth PH , Smith E . The effect of gastrointestinal hormones on the gastric microcirculation. Gastroenterology 71: 435‐438, 1976.
 188. Haglund U , Lundgren O . Reactions within consecutive vascular sections of the small intestine of the cat during prolonged hypotension. Acta Physiol Scand 84: 151, 1972.
 189. Hansen MB , Witte AB . The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol (Oxf) 193: 311‐323, 2008.
 190. Hanson KM , Johnson PC . Pressure‐flow relationships in isolated dog colon. Am J Physiol 212: 574‐578, 1967.
 191. Harris NR , Carter PR , Lee S , Watts MN , Zhang S , Grisham MB . Association between blood flow and inflammatory state in a T‐cell transfer model of inflammatory bowel disease in mice. Inflamm Bowel Dis 16: 776‐782, 2010.
 192. Harris NR , Carter PR , Yadav AS , Watts MN , Zhang S , Kosloski‐Davidson M , Grisham MB . Relationship between inflammation and tissue hypoxia in a mouse model of chronic colitis. Inflamm Bowel Dis 17: 742‐746, 2011.
 193. Harris NR , Whatley JR , Carter PR , Morgan GA , Grisham MB . Altered microvascular hemodynamics during the induction and perpetuation of chronic gut inflammation. Am J Physiol Gastrointest Liver Physiol 296: G750‐G754, 2009.
 194. Harrison R . Structure and function of xanthine oxidoreductase: Where are we now? Free Rad Biol Med 33: 774‐797, 2002.
 195. Hartleb M , Moreau R , Cailmail S , Gaudin C , Lebrec D . Vascular hyporesponsiveness to endothelin 1 in rats with cirrhosis. Gastroenterology 107: 1085‐1093, 1994.
 196. Hatoum OA , Binion DG . The vasculature and inflammatory bowel disease: Contribution to pathogenesis and clinical pathology. Inflamm Bowel Dis 11: 304‐313, 2005.
 197. Hatoum OA , Binion DG , Otterson MF , Gutterman DD . Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide‐mediated vasodilation. Gastroenterology 125: 58‐69, 2003.
 198. Hatoum OA , Heidemann J , Binion DG . The intestinal microvasculature as a therapeutic target in inflammatory bowel disease. Ann N Y Acad Sci 1072: 78‐97, 2006.
 199. Hebert MT , Marshall JM . Direct observations of responses of mesenteric microcirculation of the rat to circulating noradrenaline. J Physiol 368: 393‐407, 1985.
 200. Heer M , Repond F , Hany A , Sulser H , Kehl O , Jager K . Acute ischaemic colitis in a female long distance runner. Gut 28: 896‐899, 1987.
 201. Hei ZQ , Gan XL , Huang PJ , Wei J , Shen N , Gao WL . Influence of Ketotifen, Cromolyn Sodium, and Compound 48/80 on the survival rates after intestinal ischemia reperfusion injury in rats. BMC Gastroenterol 8: 42, 2008.
 202. Hennenberg M , Trebicka J , Kohistani AZ , Heller J , Sauerbruch T . Vascular hyporesponsiveness to angiotensin II in rats with CCl4‐induced liver cirrhosis. Eur J Clin Invest 39: 906‐913, 2009.
 203. Henningsson A , Bjiirck I , Nyman M . Short‐chain fatty acid formation at fermentation of indigestible carbohydrates. Scand J Nutrition 45: 165‐168, 2001.
 204. Henriksnas J , Phillipson M , Storm M , Engstrand L , Soleimani M , Holm L . Impaired mucus‐bicarbonate barrier in Helicobacter pylori‐infected mice. Am J Physiol Gastrointest Liver Physiol 291: G396‐G403, 2006.
 205. Henson PM , Johnston RB, Jr . Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest 79: 669, 1987.
 206. Hernandez LA , Grisham MB , Twohig B , Arfors KE , Harlan JM , Granger DN . Role of neutrophils in ischemia‐reperfusion‐induced microvascular injury. Am J Physiol 253: H699‐H703, 1987.
 207. Hill‐Eubanks DC , Gonzales AL , Sonkusare SK , Nelson MT . Vascular TRP channels: Performing under pressure and going with the flow. Physiology (Bethesda) 29: 343‐60, 2014.
 208. Hippenstiel S , Krull M , Ikemann A , Risau W , Clauss M , Suttorp N . VEGF induces hyperpermeability by a direct action on endothelial cells. Am J Physiol 274: L678‐L684, 1998.
 209. Ho CW , Beard JL , Farrell PA , Minson CT , Kenney WL . Age, fitness, and regional blood flow during exercise in the heat. J Appl Physiol 82: 1126‐1135, 1997.
 210. Holm L , Jagare A . Role of prostaglandins in regulation of gastric mucosal blood flow and acid secretion. Am J Physiol 263: G446‐G451, 1992.
 211. Holm L , Jagare A . Influence of tactile stimulation of the rat gastric mucosa on blood flow and acid output. Am J Physiol 265: G303‐G309, 1993.
 212. Holm L , Jagare A . Histamine is not involved in pentagastrin‐induced gastric mucosal vasodilation in the rat. Am J Physiol 266: G55‐G61, 1994.
 213. Holm L , Perry MA . Role of blood flow in gastric acid secretion. Am J Physiol 254: G281‐G293, 1988.
 214. Holm M , Johansson B , Pettersson A , Fandriks L . Carbon dioxide mediates duodenal mucosal alkaline secretion in response to luminal acidity in the anesthetized rat. Gastroenterology 115: 680‐685, 1998.
 215. Holm‐Rutili L , Berglindh T . Pentagastrin and gastric mucosal blood flow. Am J Physiol 250: G575‐G580, 1986.
 216. Holm‐Rutili L , Perry MA , Granger DN . Autoregulation of gastric blood flow and oxygen uptake. Am J Physiol 241: G143‐G149, 1981.
 217. Holzer P . Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43: 143‐201, 1991.
 218. Holzer P . Efferent‐like roles of afferent neurons in the gut: Blood flow regulation and tissue protection. Auton Neurosci 125: 70‐75, 2006.
 219. Holzer P . Acid sensing by visceral afferent neurones. Acta Physiol (Oxf) 201: 63‐75, 2011.
 220. Holzer P . Neural regulation of gastrointestinal blood flow. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. vol. 1, 5th ed. London: Elsevier, 2012, pp. 817‐845.
 221. Holzer P , Livingston EH , Saria A , Guth PH . Sensory neurons mediate protective vasodilatation in rat gastric mucosa. Am J Physiol 260: G363‐G370, 1991.
 222. Horie Y , Wolf R , Flores SC , McCord JM , Epstein CJ , Granger DN . Transgenic mice with increased copper/zinc‐superoxide dismutase activity are resistant to hepatic leukostasis and capillary no‐reflow after gut ischemia/reperfusion. Circ Res 83: 691‐696, 1998.
 223. Hottenstein OD , Pawlik WW , Remak G , Jacobson ED . Capsaicin‐sensitive nerves modulate reactive hyperemia in rat gut. Proc Soc Exp Biol Med 199: 311‐320, 1992.
 224. Hsieh CP , Dabney JM , Chen WT , Chou CC . Effect of lumen acidity and osmolarity on duodenal blood flow and motility (Abstract). Physiologist 13: 227, 1970.
 225. Hulten L , Lindhagen J , Lundgren O , et al. Regional intestinal blood flow in ulcerative colitis and Crohn's disease. Gastroenterology 72: 388‐396, 1977.
 226. Ibrahim CB , Aroniadis OC , Brandt LJ . On the role of ischemia in the pathogenesis of IBD: A review. Inflamm Bowel Dis 16: 696‐702, 2010.
 227. Ichikawa H , Flores S , Kvietys PR , Wolf RE , Yoshikawa T , Granger DN , Aw TY . Molecular mechanisms of anoxia/reoxygenation‐induced neutrophil adherence to cultured endothelial cells. Circ Res 81: 922‐931, 1997.
 228. Ichikawa T , Ishihara K , Kusakabe T , Hiruma H , Kawakami T , Hotta K . CGRP modulates mucin synthesis in surface mucus cells of rat gastric oxyntic mucosa. Am J Physiol Gastrointest Liver Physiol 279: G82‐G89, 2000.
 229. Im E , Choi YJ , Kim CH , Fiocchi C , Pothoulakis C , Rhee SH . The angiogenic effect of probiotic Bacillus polyfermenticus on human intestinal microvascular endothelial cells is mediated by IL‐8. Am J Physiol Gastrointest Liver Physiol 297(5): G999‐G1008, 2009.
 230. Inauen W , Payne DK , Kvietys PR , Granger DN . Hypoxia/reoxygenation increases the permeability of endothelial cell monolayers: Role of oxygen radicals. Free Radic Biol Med 9: 219‐223, 1990.
 231. Iwakiri Y , Cadelina G , Sessa WC , Groszmann RJ . Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension. Am J Physiol 283: G1074, 2002.
 232. Jacobson ED , Eisenberg MM , Swan KG . Effects of histamine on gastric blood flow in conscious dogs. Gastroenterology 51: 466‐472, 1966.
 233. Jansson G , Lundgren O , Martinson J . Neurohormonal control of gastric blood flow. Gastroenterology 58: 425‐429, 1970.
 234. Jansson EA , Petersson J , Reinders C , Sobko T , Bjorne H , Phillipson M , Weitzberg E , Holm L , Lundberg JO . Protection from nonsteroidal anti‐inflammatory drug (NSAID)‐induced gastric ulcers by dietary nitrate. Free Radic Biol Med 42: 510‐518, 2007.
 235. Jeays AD , Lawford PV , Gillott R , Spencer PA , Bardhan KD , Hose DR . A framework for the modeling of gut blood flow regulation and postprandial hyperaemia. World J Gastroenterol 13: 1393‐1398, 2007.
 236. Jerkic M , Peter M , Ardelean D , Fine M , Konerding MA , Letarte M . Dextran sulfate sodium leads to chronic colitis and pathological angiogenesis in endoglin heterozygous mice. Inflamm Bowel Dis 16: 1859‐1870, 2010.
 237. Jeukendrup AE , Vet‐Joop K , Sturk A , Stegen JH , Saris WH , Wagenmakers AJ . Relationship between gastrointestinal complaints and endotoxaemia, cytokine release and the acute‐phase reaction during and after a long‐distance triathlon in highly trained men. Clin Sci (Lond) 98: 47‐55, 2000.
 238. Jodal M , Lundgren O . Countercurrent mechanisms in the mammalian gastrointestinal tract. Gastroenterology 91: 225‐2241, 1986.
 239. Joh T , Granger DN , Benoit JN . Endogenous vasoconstrictor tone in intestine of normal and portal hypertensive rats. Am J Physiol 264: H171‐H177, 1993.
 240. Joh T , Granger DN , Benoit JN . Intestinal microvascular responsiveness to norepinephrine in chronic portal hypertension. Am J Physiol 260: H1135‐H1143, 1991.
 241. Johnson PC , Hanson KM . Capillary filtration in the small intestine of the dog. Circ Res 19: 766‐773, 1966.
 242. Jurisic G , Sundberg JP , Detmar M . Blockade of VEGF receptor‐3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis 19: 1983‐1989, 2013.
 243. Jurkovich GJ , Pitt RM , Curreri PW , Granger DN . Hypothermia prevents increased capillary permeability following ischemia‐reperfusion injury. J Surg Res 44: 514‐521, 1988.
 244. Kagawa S , Aoi M , Kubo Y , Kotani T , Takeuchi K . Stimulation by capsaicin of duodenal HCO3(−) secretion via afferent neurons and vanilloid receptors in rats: Comparison with acid‐induced HCO3(−) response. Dig Dis Sci 48: 1850‐1856, 2003.
 245. Kato S , Abe Y , Konishi M , Kuroda N , Takeuchi K . Mechanism of gastric hyperemic response during acid secretion in rats: Relation to ntric oxide, prostaglandins, and sensory neurons. J Clin Gastroenterol 25(Suppl 1): S48‐S55, 1997.
 246. Kalia N , Brown NJ , Wood RF , Pockley AG . Ketotifen abrogates local and systemic consequences of rat intestinal ischemia‐reperfusion injury. J Gastroenterol Hepatol 20: 1032‐1038, 2005.
 247. Kanwar S , Kubes P . Ischemia/reperfusion‐induced granulocyte influx is a multistep process mediated by mast cells. Microcirculation 1: 175‐82, 1994.
 248. Kanwar S , Kubes P . Mast cells contribute to ischemia‐reperfusion‐induced granulocyte infiltration and intestinal dysfunction. Am J Physiol 267: G316‐G321, 1994.
 249. Karasawa A , Guo JP , Ma XL , Tsao PS , Lefer AM . Protective actions of a leukotriene B4 antagonist in splanchnic ischemia and reperfusion in rats. Am J Physiol 261: G191‐G198, 1991.
 250. Kato M , Naruse S , Takagi T , Shionoya S . Postprandial gastric blood flow in conscious dogs. Am J Physiol 257: G111‐G117, 1989.
 251. Kato S , Tanaka A , Kunikata T , Umeda M , Takeuchi K . Protective effect of lafutidine against indomethacin‐induced intestinal ulceration in rats: Relation to capsaicin‐sensitive sensory neurons. Digestion 61(1): 39‐46, 2000.
 252. Kaunitz JD , Akiba Y . Review article: Duodenal bicarbonate ‐ mucosal protection, luminal chemosensing and acid‐base balance. Aliment Pharmacol Ther 24(Suppl 4): 169‐176, 2006.
 253. Kawabata A , Kinoshita M , Nishikawa H , Kuroda R , Nishida M , Araki H , Arizono N , Oda Y , Kakehi K . The protease‐activated receptor‐2 agonist induces gastric mucus secretion and mucosal cytoprotection. J Clin Invest 107: 1443‐1450, 2001.
 254. Kawano S , Tsuji S . Role of mucosal blood flow: A conceptional review in gastric mucosal injury and protection. J Gastroenterol Hepatol 15(Suppl): D1‐D6, 2000.
 255. Kenney WL , Ho CW . Age alters regional distribution of blood flow during moderate‐intensity exercise. J Appl Physiol 79: 1112‐1119, 1995.
 256. Kiel J , Pitts V , Benoit J , Granger D , Shepherd A . Reduced vascular sensitivity to norepinephrine in portal hypertensive rats. Am J Physiol 248: G192, 1985.
 257. Kiel JW , Riedel GL , DiResta GR , Shepherd AP . Gastric mucosal blood flow measured by laser‐Doppler velocimetry. Am J Physiol 249: G539‐G545, 1985.
 258. Kiel JW , Riedel GL , Shepherd AP . Local control of canine gastric mucosal blood flow. Gastroenterology 93: 1041‐1053, 1987.
 259. Kiel JW , Shepherd AP . Gastric oxygen uptake during autoregulatory escape from sympathetic stimulation. Am J Physiol 257: G633‐G636, 1989.
 260. Kim H , Kataru RP , Koh GY . Inflammation‐associated lymphangiogenesis: A double‐edged sword? J Clin Invest 124: 936‐942, 2014.
 261. Kimura T , Fujiyama Y , Sasaki M , Andoh A , Fukuda M , Nakajima S , Bamba T . The role of mucosal mast cell degranulation and free‐radical generation in intestinal ischaemia‐reperfusion injury in rats. Eur J Gastroenterol Hepatol 10: 659‐666, 1998.
 262. Kitano S , Koyanagi N , Suimachi K , Kobayachi M , Inokuchi K . Mucosal blood flow and modified vascular responses to norepinephrine in the stomach of rats with liver cirrhosis. Eur Surg Res 14: 221, 1982.
 263. Kivilaakso E , Silen W . The role of mucosal carbonic anhydrase in the protection of gastric mucosa against luminal H+ . Scand J Gastroenterol Suppl 67: 219‐221, 1981.
 264. Kokura S , Wolf RE , Yoshikawa T , Granger DN , Aw TY Molecular mechanisms of neutrophil‐endothelial cell adhesion induced by redox imbalance. Circ Res 84: 516‐524, 1999.
 265. Komatsu S , Berg RD , Russell JM , Nimura Y , Granger DN . Enteric microflora contribute to constitutive ICAM‐1 expression on vascular endothelial cells. Am J Physiol Gastrointest Liver Physiol 279(1): G186‐G191, 2000.
 266. Kopanakis N , Saiti A , D'Avgerinos E , Masselou K , Simiri M , Mandaraka A , Vasiliadis G , Katergiannakis V . Serum VEGF and bFGF in patients with inflammatory bowel diseases. Ann Ital Chir 85: 203‐206, 2014.
 267. Korthuis RJ , Benoit JN , Kvietys PR , Townsley MI , Taylor AE , Granger DN . Humoral factors may mediate increased rat hindquarter blood flow in portal hypertension. Am J Physiol 249: H827‐H833, 1985.
 268. Koutroubakis IE , Tsiolakidou G , Karmiris K , Kouroumalis EA . Role of angiogenesis in inflammatory bowel disease. Inflamm Bowel Dis 12: 515‐523, 2006.
 269. Kravetz D , Arderiu M , Bosch J , Fuster J , Visa J , Casamitjana R , Rodes J . Hyperglucagonemia and hyperkinetic circulation after portocaval shunt in the rat. Am J Physiol 252: G257, 1987.
 270. Krzystek‐Korpacka M , Neubauer K , Matusiewicz M . Platelet derived growth factor‐BB reflects clinical, inflammatory and angiogenic disease activity and oxidative stress in inflammatory bowel disease. Clin Biochem 42: 1602‐1609, 2009.
 271. Kubes P , Granger DN . Leukocyte‐endothelial cell interactions evoked by mast cells. Cardiovasc Res 32: 699‐708, 1996.
 272. Kubes P , Hunter J , Granger DN Ischemia/reperfusion‐induced feline intestinal dysfunction: Importance of granulocyte recruitment. Gastroenterology 103: 807‐812, 1992.
 273. Kubes P , Ibbotson G , Russell J , Wallace JL , Granger DN . Role of platelet‐activating factor in ischemia/reperfusion‐induced leukocyte adherence. Am J Physiol 259: G300‐G305, 1990.
 274. Kubes P , Suzuki M , Granger DN . Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88: 4651‐4655, 1991.
 275. Kumar P , Shen Q , Pivetti CD , Lee ES , Wu MH , Yuan SY . Molecular mechanisms of endothelial hyperpermeability: Implications in inflammation. Expert Rev Mol Med 11: e19, 2009.
 276. Kurose I , Anderson DC , Miyasaka M , et al. Molecular determinants of reperfusion‐induced leukocyte adhesion and vascular protein leakage. Circ Res 74: 336‐343, 1994.
 277. Kurose I , Kubes P , Wolf R , Anderson DC , Paulson J , Miyasaka M , Granger DN . Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage. Circ Res 73: 164‐171, 1993.
 278. Kurose I , Wolf R , Grisham MB , Granger DN . Modulation of ischemia/reperfusion‐induced microvascular dysfunction by nitric oxide. Circ Res 74: 376‐382, 1994.
 279. Kurtel H , Tso P , Granger DN . Granulocyte accumulation in postischemic intestine: Role of leukocyte adhesion glycoprotein CD11/CD18. Am J Physiol 262: G878‐G882, 1992.
 280. Kvietys PR . The gastrointestinal circulation. In: Granger DN , Granger JP , editors. Integrated Systems Physiology: From Molecule to Function. San Rafael (CA): Morgan & Claypool Life Sciences, 2010, pp. 1‐127.
 281. Kvietys PR . Physiology of the gastrointestinal microcirculation. PanVascular Medicine, Berlin, Heidelberg: Springer‐Verlag Berlin Heidelberg, 2014.
 282. Kvietys PR , Barrowman JA , Harper SL , Granger DN . Relations among canine intestinal motility, blood flow, and oxygenation. Am J Physiol 251: G25‐G33, 1986.
 283. Kvietys PR , Barrowman JA , Harper SL , Granger DN . Relations among canine intestinal motility, blood flow, and oxygenation. Am J Physiol 251: G25‐G33, 1986.
 284. Kvietys PR , Gallavan RH , Chou CC . Contribution of bile to postprandial intestinal hyperemia. Am J Physiol 238: G284‐G288, 1980.
 285. Kvietys PR , Granger DN . Effects of solute‐coupled fluid absorption on blood flow and oxygen uptake in the dog colon. Gastroenterology 81: 450‐457, 1981.
 286. Kvietys PR , Granger DN . Effect of volatile fatty acids on blood flow and oxygen uptake by the dog colon. Gastroenterology 80: 962‐969, 1981.
 287. Kvietys PR , Granger DN . Endothelial cell monolayers as a tool for studying microvascular pathophysiology. Am J Physiol 273: G1189‐G1199, 1997.
 288. Kvietys PR , Granger DN . Regulation of colonic blood flow. Fed Proc 41: 2106‐2110, 1982.
 289. Kvietys PR , Granger DN . Relation between intestinal blood flow and oxygen uptake. Am J Physiol 242: G202‐G208, 1982.
 290. Kvietys PR , Granger DN . Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Radic Biol Med 52: 556‐592, 2012.
 291. Kvietys PR , Granger DN . The splanchnic circulation. In: Reinus JF , Simon D , editors. Gastrointestinal Anatomy and Physiology: The Essentials. Hoboken: Wiley‐Blackwell, 2014, pp. 149‐163.
 292. Kvietys PR , Granger DN . Vasoactive agents and splanchnic oxygen uptake. Am J Physiol 243: G1‐G9, 1982.
 293. Kvietys PR , McLendon JM , Granger DN . Postprandial intestinal hyperemia: Role of bile salts in the ileum. Am J Physiol 241: G469‐G477, 1981.
 294. Kvietys PR , Miller T , Granger DN . Intrinsic control of colonic blood flow and oxygenation. Am J Physiol 238: G478‐G484, 1980.
 295. Kvietys PR , Perry MA , Granger DN . Intestinal capillary exchange capacity and oxygen delivery‐to‐demand ratio. Am J Physiol 245: G635‐G640, 1983.
 296. Kvietys, PR , Pittman R , Chou CC . Contribution of luminal concentration of nutrients and osmolality to postprandial hyperemia in dogs. Proc Soc Exp Biol Med 152: 659‐663, 1976.
 297. Kvietys PR , Specian RD , Grisham MB , Tso P . Jejunal mucosal injury and restitution: Role of hydrolytic products of food digestion. Am J Physiol 261: G384‐G391, 1991.
 298. Kvietys PR , Wilborn WH , Granger DN . Effect of atropine on bile‐oleic acid‐induced alterations in dog jejunal hemodynamics, oxygenation, and net transmucosal water movement. Gastroenterology 18(80): 31‐38, 1981.
 299. Kvietys PR , Yaqinuddin A , AlKattan W . Gastrointestinal Mucosal Defense System. In: Granger DN , Granger JP , editors. Integrated Systems Physiology: From Molecule to Function. San Rafael (CA): Morgan & Claypool Life Sciences, 2015, pp. 1‐172.
 300. Lambert GP , Broussard LJ , Mason BL , Mauermann WJ , Gisolfi CV . Gastrointestinal permeability during exercise: Effects of aspirin and energy containing beverages. J Appl Physiol 90: 2075‐2080, 2001.
 301. Lang DJ , Johnson PC . Elevated ambient oxygen does not affect autoregulation in cat mesentery. Am J Physiol 255: H131‐H137, 1988.
 302. Laroux FS , Grisham MB . Immunological basis of inflammatory bowel disease: Role of the microcirculation. Microcirculation 8: 283‐301, 2001.
 303. Lee F , Colombato L , Albillos A , Groszmann R . Administration of Nv2nitro‐l‐arginine ameliorates portal‐systemic shunting in portal hypertensive rats. Gastroenterology 105: 1464‐1470, 1993.
 304. Lee S , Carter PR , Watts MN , Bao JR , Harris NR . Effects of the endothelin‐converting enzyme inhibitor SM‐19712 in a mouse model of dextran sodium sulfate‐induced colitis. Inflamm Bowel Dis 15: 1007‐1013, 2009.
 305. Lenaerts K , Ceulemans LJ , Hundscheid IH , Grootjans J , Dejong CH , Olde Damink SW . New insights in intestinal ischemia‐reperfusion injury: Implications for intestinal transplantation. Curr Opin Organ Transplant 18: 298‐303, 2013.
 306. Leung FW . Modulation of autoregulatory escape by capsaicin‐sensitive afferent nerves in rat stomach. Am J Physiol 262: H562‐H567, 1992.
 307. Leung FW , Guth PH . Dissociated effects of somatostatin on gastric acid secretion and mucosal blood flow. Am J Physiol 248 :G337‐G341, 1985.
 308. Leung FW , Kauffman GL Jr , Washington J , Scremin OU , Guth PH . Blood flow limitation of stimulated gastric acid secretion in the rat. Am J Physiol 250: G794‐G799, 1986.
 309. Levine SE , Granger DN , Brace RA , Taylor AE . Effect of hyperosmolality on vascular resistance and lymph flow in the cat ileum. Am J Physiol 234: H14‐H20, 1978.
 310. Levitt DG , Bond JH , Levitt MD . Use of a model of small bowel mucosa to predict passive absorption. Am J Physiol 239: G23‐G29, 1980.
 311. Lewis MS , Whatley RE , Cain P , McIntyre TM , Prescott SM , Zimmerman GA . Hydrogen peroxide stimulates the synthesis of platelet‐activating factor by endothelium and induces endothelial cell‐dependent neutrophil adhesion. J Clin Invest 82: 2045, 1988.
 312. Lidington D , Schubert R , Bolz SS . Capitalizing on diversity: An integrative approach towards the multiplicity of cellular mechanisms underlying myogenic responsiveness. Cardiovasc Res 97: 404‐412, 2013.
 313. Lippe IT , Holzer P . Participation of endothelium‐derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back‐diffusion. Br J Pharmacol 105: 708‐714, 1992.
 314. Lopez‐Quintero SV , Cancel LM , Pierides A , Antonetti D , Spray DC , Tarbell JM . High glucose attenuates shear‐induced changes in endothelial hydraulic conductivity by degrading the glycocalyx. PLoS One 8(11): e78954, 2013.
 315. Lopez‐Talavera J , Cadelina G , Olchowski J , Merrill W , Groszmann R . Thalidomide inhibits tumor necrosis factor‐a, decreases nitric oxide synthesis and ameliorates the hyperdynamic circulatory syndrome in portal hypertensive rats. Hepatology 23: 1616‐1621, 1996.
 316. Lopez‐Talavera J , Merrill W , Groszmann R . Tumor necrosis factor‐a: A major contributor to the hyperdynamic circulation in prehepatic portal‐hypertensive rats. Gastroenterology 108: 761‐767, 1995.
 317. Loufrani L , Henrion D . Role of the cytoskeleton in flow (shear stress)‐induced dilation and remodeling in resistance arteries. Med Biol Eng Comput 46: 451‐460, 2008.
 318. Lucas W , Schroy PC III . Reversible ischemic colitis in a high endurance athlete. Am J Gastroenterol 93: 2231‐2234, 1998.
 319. Lundberg JO , Weitzberg E , Gladwin MT . The nitrate‐nitrite‐nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7: 156‐167, 2008.
 320. Lundberg JO , Weitzberg E , Lundberg JM , Alving K . Intragastric nitric oxide production in humans: Measurements in expelled air. Gut 35: 1543‐1546, 1994.
 321. Lundgren O , Svanvik J . Mucosal hemodynamics in the small intestine of the cat during reduced perfusion pressure. Acta Physiol Scand 88: 551‐63, 1973.
 322. Luo XJ , Liu B , Dai Z , Yang ZC , Peng J . Stimulation of calcitonin gene‐related peptide release through targeting capsaicin receptor: A potential strategy for gastric mucosal protection. Dig Dis Sci 58(2): 320‐325, 2013.
 323. Lutz J , Biester J . The reactions of the gastric vascular bed on venous or arterial pressure elevation and their comparison with values of the splenic and intestinal circulatory system. Veno‐vasomotoric reaction and autoregulation Pflugers Arch 330: 230‐242, 1971.
 324. Macedo MP , Lautt WW . Autoregulatory capacity in the superior mesenteric artery is attenuated by nitric oxide. Am J Physiol 271: G400‐G404, 1996.
 325. Madsen JL , Sondergaard SB , Moller S . Meal‐induced changes in splanchnic blood flow and oxygen uptake in middle‐aged healthy humans. Scand J Gastroenterol 41: 87‐92, 2006.
 326. Mahl TC , Groszmann RJ . Pathophysiology of portal hypertension and variceal bleeding. Surg Clin North Am 70: 251, 1990.
 327. Mangino MJ , Anderson CB , Murphy MK , Brunt E , Turk J . Mucosal arachidonate metabolism and intestinal ischemia‐reperfusion injury. Am J Physiol 257: G299‐G307, 1989.
 328. Matheson PJ , Wilson MA , Spain DA , Harris PD , Anderson GL , Garrison RN . Glucose‐induced intestinal hyperemia is mediated by nitric oxide. J Surg Res 72: 146‐154, 1997.
 329. McAllister RM . Adaptations in control of blood flow with training: Splanchnic and renal blood flows. Med & Sci Sports & Exercise 30: 375‐381, 1998.
 330. McAllister RM , Kimani JK , Webster JL , Parker JL , Laughlin MH . Effects of exercise training on responses of peripheral and visceral arteries in swine. J Appl Physiol 80: 216‐225, 1996.
 331. McCafferty DM , Smith CW , Granger DN , Kubes P . Intestinal inflammation in adhesion molecule‐deficient mice: An assessment of P‐selectin alone and in combination with ICAM‐1 or E‐selectin. J Leukoc Biol 66: 67‐74, 1999.
 332. McNeill JR . Redundant nature of the vasopressin and renin–angiotensin systems in the control of mesenteric resistance vessels of the conscious fasted cat. Can J Physiol Pharmacol 61: 770‐773, 1983.
 333. Mesh CL , Joh T , Korthuis RJ , Granger DN , Benoit JN . Intestinal vascular sensitivity to vasopressin in portal hypertensive rats. Gastroenterology 100: 916‐921, 1991.
 334. Michels NA , Siddharth P , Kornblith PL , Parke WW . Routes of collateral circulation of the gastrointestinal tract as ascertained in a dissection of 500 bodies. Int Surg 49: 8‐28, 1986.
 335. Mensink PB , Geelkerken RH , Huisman AB , Kuipers EJ , Kolkman JJ . Effect of various test meals on gastric and jejunal carbon dioxide: A study in healthy subjects. Scand J Gastroenterol 41: 1290‐1298, 2006.
 336. Miyoshi M , Kasahara E , Park AM , Hiramoto K , Minamiyama Y , Takemura S , Sato EF , Inoue M . Dietary nitrate inhibits stress‐induced gastric mucosal injury in the rat. Free Radic Res 37: 85‐90, 2003.
 337. Moghadamrad S , McCoy KD , Geuking MB , Sägesser H , Kirundi J , Macpherson AJ , De Gottardi A . Attenuated portal hypertension in germ‐free mice: Function of bacterial flora on the development of mesenteric lymphatic and blood vessels. Hepatology 61(15): 1685‐1695, 2015.
 338. Montrose DC , Scherl EJ , Bosworth BP , Zhou XK , Jung B , Dannenberg AJ , Hla T . S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J Lipid Res 54: 843‐851, 2013.
 339. More N , Lobsotomayor G , Basse‐Cathalinat B , Christiane B , Balabaud C . Splanchnic arterial blood flow in rats with portocaval shunts. Am J Physiol 246: G331, 1984.
 340. Mori M , Salter JW , Vowinkel T , Krieglstein CF , Stokes KY , Granger DN . Molecular determinants of the prothrombogenic phenotype assumed by inflamed colonic venules. Am J Physiol Gastrointest Liver Physiol 288: G920‐G926, 2005.
 341. Mori M , Stokes KY , Vowinkel T , Watanabe N, Elrod JW, Harris NR, Lefer DJ, Hibi T, Granger DN. Colonic blood flow responses in experimental colitis: Time course and underlying mechanisms. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005.
 342. Mortillaro NA , Granger HJ . Reactive hyperemia and oxygen extraction in the feline small intestine. Circ Res 41: 859‐865, 1977.
 343. Mortillaro NA , Mustafa SJ . Possible role of adenosine in intestinal reactive hyperemia. Federation Proc 37: 874, 1978.
 344. Mortillaro NA , Taylor AE . Interaction of capillary and tissue forces in the cat small intestine. Circ Res 39: 348‐358, 1976.
 345. Moses T , Wagner L , Fleming SD . TLR4‐mediated Cox‐2 expression increases intestinal ischemia/reperfusion‐induced damage. J Leukoc Biol 86: 971‐980, 2009.
 346. Nakamura M , Asada M , Matsui H , Hibi N , Tsuchimoto K , Inoue J , Oda M . Increased microvascular permeability in early stage of dextran sulfate sodium‐induced colitis: Its interaction with lansoprazole binding sites. Clin Hemorheol Microcirc 34: 193‐199, 2006.
 347. Naruse S , Takagi T , Kato M , Ozaki T . Interdigestive gastric blood flow: The relation to motor and secretory activities in conscious dogs. Exp Physiol 77: 701‐708, 1992.
 348. Nezu Y , Nezu Y , Shigihara K , Harada Y , Yogo T , Hara Y , Tagawa M . Effects of small intestinal ischemia and reperfusion on expression of tumor necrosis factor‐alpha and interleukin‐6 messenger RNAs in the jejunum, liver, and lungs of dogs. Am J Vet Res 69: 512‐518, 2008.
 349. Nguyen LS , Villablanca AC , Rutledge JC . Substance P increases microvascular permeability via nitric oxide‐mediated convective pathways. Am J Physiol 268: R1060‐R1068, 1995.
 350. Niederberger M , Martin P , Gines P , Morris K , Tsai P , Xu D , Mc‐Murty I , Schrier R . Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology 109: 1624‐1630, 1995.
 351. Nilsson UA , Olsson LI , Thor H , Moldeus P , Bylund‐Fellenius AC . Detection of oxygen radicals during reperfusion of intestinal cells in vitro. Free Radic Biol Med 6: 251‐259, 1989.
 352. Norris CP , Barnes GE , Smith EE , Granger HJ . Autoregulation of superior mesenteric flow in fasted and fed dogs. Am J Physiol 237: H174‐H177, 1979.
 353. Nyachoti CM , de Lange CFM , McBride BW , Leeson S , Schulze H . Dietary influence on organ size and in vitro oxygen consumption by visceral organs of growing pigs. Livest Prod Sci 65: 229‐237, 2000.
 354. Nyhof RA , Chou CC . Evidence against local neural mechanism for intestinal postprandial hyperemia. Am J Physiol 245: H437‐H446, 1983.
 355. Nyhof RA , Ingold‐Wilcox D , Chou CC . Effect of atropine on digested food‐induced intestinal hyperemia. Am J Physiol 249: G685‐G690, 1985.
 356. Nyhof RA , Rascoe TG , Granger HJ . Acute local effects of angiotensin II on the intestinal vasculature. Hypertension 6: 13‐19, 1984.
 357. Nylander O , Kvietys P , Granger DN . Effects of hydrochloric acid on duodenal and jejunal mucosal permeability in the rat. Am J Physiol 257: G653‐G660, 1989.
 358. Ohkubo H , Okuda K , Iida S , Ohnishi K , Ikawa S , Makino I . Role of portal vein shunts and impaired hepatic extraction in the serum elevated bile acids in liver cirrhosis. Gastroenterology 86: 514, 1984.
 359. Oikonomou KA , Kapsoritakis AN , Kapsoritaki AI , Manolakis AC , Tiaka EK , Tsiopoulos FD , Tsiompanidis IA , Potamianos SP . Angiogenin, angiopoietin‐1, angiopoietin‐2, and endostatin serum levels in inflammatory bowel disease. Inflamm Bowel Dis 17: 963‐970, 2011.
 360. Oliver MG , Specian RD , Perry MA , Granger DN . Morphologic assessment of leukocyte‐endothelial cell interactions in mesenteric venules subjected to ischemia and reperfusion. Inflammation 15: 331‐346, 1991.
 361. Osawa M , Masuda M , Kusano K , Fujiwara K . Evidence for a role of platelet endothelial cell adhesion molecule‐1 in endothelial cell mechanosignal transduction: Is it a mechanoresponsive molecule? J Cell Biol 158: 773‐785, 2002.
 362. Otte JA , Oostveen E , Geelkerken RH , Groeneveld AB , Kolkman JJ . Exercise induces gastric ischemia in healthy volunteers: A tonometry study. J Appl Physiol 91: 866‐871, 2001.
 363. Ozaki M , Kawashima S , Hirase T , Yamashita T , Namiki M , Inoue N , Hirata K , Yokoyama M . Overexpression of endothelial nitric oxide synthase in endothelial cells is protective against ischemia‐reperfusion injury in mouse skeletal muscle. Am J Pathol 160: 1335‐1344, 2002.
 364. Parks DA , Bulkley GB , Granger DN , Hamilton SR , McCord JM . Ischemic injury in the cat small intestine: Role of superoxide radicals. Gastroenterology 82: 9, 1982.
 365. Parks DA , Granger DN Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 250: G749‐G753, 1986.
 366. Parks DA , Granger DN Ischemia‐induced vascular changes: Role of xanthine oxidase and hydroxyl radicals. Am J Physiol 245: G285‐G289, 1983.
 367. Parks DA , Granger DN . Xanthine oxidase: Biochemistry, distribution and physiology. Acta Physiol Scand Suppl 548: 87‐99, 1986.
 368. Parks DA , Granger DN , Bulkley GB , Shah AK . Soybean trypsin inhibitor attenuates ischemic injury to the feline small intestine. Gastroenterology 89: 6‐12, 1985.
 369. Parks DA , Grogaard B , Granger DN . Comparison of partial and complete arterial occlusion models for studying intestinal ischemia. Surgery 92: 896, 1982.
 370. Parks DA , Shah AK , Granger DN . Oxygen radicals: Effects on intestinal vascular permeability. Am J Physiol 247: G167‐G170, 1984.
 371. Parks DA , Williams TK , Beckman JS . Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: A reevaluation. Am J Physiol 254: G768‐G774, 1988.
 372. Pawlik WW , Fondacaro JD , Jacobson ED . Metabolic hyperemia in canine gut. Am J Physiol 239: G12‐G17, 1980.
 373. Pawlik WW , Gustaw P , Jacobson ED , Sendur R , Czarnobilski K . Nitric oxide mediates intestinal hyperaemic responses to intraluminal bile‐oleate. Pflugers Arch 429: 301‐305, 1995.
 374. Pawlik WW , Hottenstein OD , Palen TE , Pawlik T , Jacobson ED . Adenosine modulates reactive hyperemia in rat gut. J Physiol Pharmacol 44: 119‐37, 1993.
 375. Pawlik W , Shepherd AP , Jacobson ED . Effect of vasoactive agents on intestinal oxygen consumption and blood flow in dogs. J Clin Invest 56: 484‐490, 1975.
 376. Perry MA , Ardell JL , Barrowman JA , Kvietys PR . Physiology of the Splanchnic Circulation. In: Kvietys PR , Barrowman JA , Granger DN , editors. Pathophysiology of the Splanchnic Circulation. Boca Raton: CRC Press, 1987, pp. 1‐56.
 377. Perry MA , Bulkley GB , Kvietys PR , Granger DN . Regulation of oxygen uptake in resting and pentagastrin‐stimulated canine stomach. Am J Physiol 242: G565‐G569, 1982.
 378. Perry MA , Granger DN . Regulation of capillary exchange capacity in the dog stomach. Am J Physiol 248: G437‐G442, 1985.
 379. Perry MA , Haedicke GJ , Bulkley GB , Kvietys PR , Granger DN . Relationship between acid secretion and blood flow in the canine stomach: Role of oxygen consumption. Gastroenterology 85: 529‐534, 1983.
 380. Peters HP , Bos M , Seebregts L , et al. Gastrointestinal symptoms in longdistance runners, cyclists, and triathletes: Prevalence, medication, and etiology. Am J Gastroenterol 94: 1570‐1581, 1999.
 381. Peters HP , De Vries WR , Vanberge‐Henegouwen GP , Akkermans LM . Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract. Gut 48: 435‐439, 2001.
 382. Petersson J , Carlstrom M , Schreiber O , Phillipson M , Christoffersson G , Jagare A , Roos S , Jansson EA , Persson AE , Lundberg JO , et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med 46: 1068‐1075, 2009.
 383. Petersson J , Phillipson M , Jansson EA , Patzak A , Lundberg JO , Holm L . Dietary nitrate increases gastric mucosal blood flow and mucosal defense. Am J Physiol Gastrointest Liver Physiol 292: G718‐G724, 2007.
 384. Petersson J , Schreiber O , Steege A , Patzak A , Hellsten A , Phillipson M , Holm L . eNOS involved in colitis‐induced mucosal blood flow increase. Am J Physiol 293: G1281‐G1287, 2007.
 385. Phillipson M , Atuma C , Henriksnas J , Holm L . The importance of mucus layers and bicarbonate transport in preservation of gastric juxtamucosal pH. Am J Physiol Gastrointest Liver Physiol 282: G211‐G219, 2002.
 386. Phillipson M , Henriksnas J , Holstad M , Sandler S , Holm L . Inducible nitric oxide synthase is involved in acid‐induced gastric hyperemia in rats and mice. Am J Physiol Gastrointest Liver Physiol 285: G154‐G162, 2003.
 387. Picarella D , Hurlbut P , Rottman J , Shi X , Butcher E , Ringler DJ . Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol 158: 2099‐2106, 1997.
 388. Pickett JP , Pendergrass RE , Bradford WD , Elchlepp JG . Localization of xanthine oxidase in rat duodenum; fixation of sections instead of blocks. Stain Technol 45: 35‐36, 1970.
 389. Pique JM , Esplugues JV , Whittle BJ . Endogenous nitric oxide as a mediator of gastric mucosal vasodilatation during acid secretion. Gastroenterology 102: 168‐174, 1992.
 390. Pique JM , Leung FW , Tan HW , Livingston E , Scremin OU , Guth PH . Gastric mucosal blood flow response to stimulation and inhibition of gastric acid secretion. Gastroenterology 95(3): 642‐650, 1988.
 391. Pizcueta MP , Casamitjana R , Bosch J , Rodes J . Decreased systemic vascular sensitivity to norepinephrine in portal hypertensive rats: Role of hyperglucagonism. Am J Physiol 258: G191‐G195, 1990.
 392. Pizcueta P , Pique J , Fernandez M , Bosch J , Rodes J , Whittle B , Moncada S . Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology 103: 1909‐1915, 1992.
 393. Pohl U , Herlan K , Huang A , Bassenge E . EDRF‐mediated shear‐induced dilation opposes myogenic vasoconstriction in small rabbit arteries. Am J Physiol 261: H2016‐H2023, 1991.
 394. Pousa ID , Maté J , Gisbert JP . Angiogenesis in inflammatory bowel disease. Eur J Clin Invest 38: 73‐81, 2008.
 395. Premen AJ , Banchs V , Womack WA , Kvietys PR , Granger DN . Importance of collateral circulation in the vascularly occluded feline intestine. Gastroenterology 92: 1215‐9, 1987.
 396. Proctor KG . Contribution of hyperosmolality to glucose‐induced intestinal hyperemia. Am J Physiol 248: G521‐G525, 1985.
 397. Proctor KG . Possible role for adenosine on local regulation of absorptive hyperemia in rat intestine. Circ Res 59: 474‐481, 1986.
 398. Qamar MI , Read AE . Effects of exercise on mesenteric blood flow in man. Gut 28: 583‐587, 1987.
 399. Rahier JF , De Beauce S , Dubuquoy L , Erdual E , Colombel JF , Jouret‐Mourin A , Geboes K , Desreumaux P . Increased lymphatic vessel density and lymphangiogenesis in inflammatory bowel disease. Aliment Pharmacol Ther 34: 533‐543, 2011.
 400. Rashid SK , Khodja NI , Auger C , Alhosin M , Boehm N , Oswald‐Mammosser M , Schini‐Kerth VB . Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: Role of the angiotensin system. PLoS One 9(5): e97458, 2014.
 401. Razack S , D'Agnillo F , Chang TM . Crosslinked hemoglobin‐superoxide dismutase‐catalase scavenges free radicals in a rat model of intestinal ischemia‐reperfusion injury. Artif Cells Blood Substit Immobil Biotechnol 25: 181‐192, 1997.
 402. Rehrer NJ , Smets A , Reynaert H , Goes E , De MK . Effect of exercise on portal vein blood flow in man. Med Sci Sports Exerc 33: 1533‐1537, 2001.
 403. Remak G , Hottenstein OD , Jacobson ED . Sensory nerves mediate neurogenic escape in rat gut. Am J Physiol 258: H778‐H786, 1990.
 404. Riaz AA , Wan MX , Schäfer T , Dawson P , Menger MD , Jeppsson B , Thorlacius H . Allopurinol and superoxide dismutase protect against leucocyte‐endothelium interactions in a novel model of colonic ischaemia‐reperfusion. Br J Surg 89: 1572‐1580, 2002.
 405. Richardson PD , Granger DN , Kvietys PR . Effects of norepinephrine, vasopressin, isoproterenol, and histamine on blood flow, oxygen uptake, and capillary filtration coefficient in the colon of the anesthetized dog. Gastroenterology 78: 1537‐1544, 1980.
 406. Richardson PD , Granger DN , Taylor AE . Capillary filtration coefficient: The technique and its application to the small intestine. Cardiovasc Res 13: 547‐561, 1979.
 407. Rijcken E , Mennigen RB , Schaefer SD , Laukoetter MG , Anthoni C , Spiegel HU , Bruewer M , Senninger N , Krieglstein CF . PECAM‐1 (CD 31) mediates transendothelial leukocyte migration in experimental colitis. Am J Physiol Gastrointest Liver Physiol 293: G446‐G452, 2007.
 408. Robinson JW , Mirkovitch V . The roles on intraluminal oxygen and glucose in the protection of the rat intestinal mucosa from the effects of ischaemia. Biomedicine 27: 60, 1977.
 409. Rocha BS , Gago B , Barbosa RM , Laranjinha J . Diffusion of nitric oxide through the gastric wall upon reduction of nitrite by red wine: Physiological impact. Nitric Oxide 22: 235‐241, 2010.
 410. Ross IN , Bahari HM , Turnberg LA . The pH gradient across mucus adherent to rat fundic mucosa in vivo and the effect of potential damaging agents. Gastroenterology 81: 713‐718, 1981.
 411. Roy TK , Secomb TW . Functional sympatholysis and sympathetic escape in a theoretical model for blood flow regulation. Front Physiol 5: 192, 2014.
 412. Rozsa Z , Jacobson ED . Capsaicin‐sensitive nerves are involved in bile‐oleate‐induced intestinal hyperemia. Am J Physiol 256: G476‐G481, 1989.
 413. Rudic R , Shesely E , Maeda N , Smithies O , Segal S , Sessa W . Direct evidence for the importance of endothelium‐derived nitric oxide in vascular remodeling. J Clin Invest 101: 731‐736, 1998.
 414. Rumbaut RE , Wang J , Huxley VH . Differential effects of l‐NAME on rat venular hydraulic conductivity. Am J Physiol Heart Circ Physiol 279: H2017‐H2023, 2000.
 415. Rune SJ , Henriksen FW . Carbon dioxide tensions in the proximal part of the canine gastrointestinal tract. Gastroenterology 56: 758‐762, 1969.
 416. Russell J , Epstein CJ , Grisham MB , Alexander JS , Yeh KY , Granger DN . Regulation of E‐selectin expression in postischemic intestinal microvasculature. Am J Physiol Gastrointest Liver Physiol 278: G878‐G885, 2000.
 417. Rutella S , Vetrano S , Correale C , Graziani C , Sturm A , Spinelli A , De Cristofaro R , Repici A , Malesci A , Danese S . Enhanced platelet adhesion induces angiogenesis in intestinal inflammation and inflammatory bowel disease microvasculature. J Cell Mol Med 15: 625‐634, 2011.
 418. Sababi M , Holm L . Villus tip microcirculation in the rat duodenum. Act Physiol Scand 154: 221‐233, 1995.
 419. Sakamoto A , Ohnishi ST , Ohnishi T , Ogawa R . Free radical formation during splanchnic artery occlusion shock. J Anesth 6: 414‐425, 1992.
 420. Salvemini D , Masini E , Pistelli A , Mannaioni PF , Vane J . Nitric oxide: A regulatory mediator of mast cell reactivity. J Cardiovasc Pharmacol 17(Suppl. 3): S258, 1991.
 421. Sanchez LD , Corwell B , Berkoff D . Medical problems of marathon runners. Am J Emerg Med 24: 608‐615, 2006.
 422. Sandblom E , Davison W , Axelsson M . Cold physiology: Postprandial blood flow dynamics and metabolism in in the Antarctic fish Pagothenia borchgrevinki. PLoS One 7(3): e33487, 2012.
 423. Santen S , Wang Y , Laschke MW , Menger MD , Jeppsson B , Thorlacius H . Rho‐kinase signaling regulates CXC chemokine formation and leukocyte recruitment in colonic ischemia‐reperfusion. Int J Colorectal Dis 25: 1063‐1070, 2010.
 424. Sawmiller DR , Chou CC . Adenosine plays a role in food‐induced jejunal hyperemia. Am J Physiol 255: G168‐G174, 1988.
 425. Sawmiller DR , Chou CC . Jejunal adenosine increases during food‐induced jejunal hyperemia. Am J Physiol 258: G370‐G376, 1990.
 426. Sawmiller DR , Chou CC . Role of adenosine in postprandial and reactive hyperemia in canine jejunum. Am J Physiol 263: G487‐G493, 1992.
 427. Scaldaferri F , Vetrano S , Sans M , Arena V , Straface G , Stigliano E , Repici A , Sturm A , Malesci A , Panes J , Yla‐Herttuala S , Fiocchi C , Danese S . VEGF‐A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 136(2): 585‐595, 2009.
 428. Schmid‐Schonbein GW , Hugli TE . A new hypothesis for microvascular inflammation in shock and multiorgan failure: Self‐digestion by pancreatic enzymes. Microcirculation 12: 71‐82, 2005.
 429. Schoenberg MH , Beger HG . Reperfusion injury after intestinal ischemia. Crit Care Med 21: 1376‐186, 1993.
 430. Schoenberg MH , Fredholm BB , Haglund U , Jung H , Sellin D , Younes M , Schildberg FW . Studies on the oxygen radical mechanism involved in the small intestinal reperfusion damage. Acta Physiol Scand 124: 581‐589, 1985.
 431. Schrieber O , Petersson J , Phillipson M , Perry M , Roos S , Holm L . Lactobacillus reuteri prevents colitis by reducing P‐selectin‐associated leukocyte‐ and platelet‐endothelial cell interactions. Am J Physiol Gastrointest Liver Physiol 296: G534‐G542, 2009.
 432. Scotland RS , Chauhan S , Davis C , De Felipe C , Hunt S , Kabir J , Kotsonis P , Oh U , Ahluwalia A . Vanilloid receptor TRPV1, sensory C‐fibers, and vascular autoregulation: A novel mechanism involved in myogenic constriction. Circ Res 95: 1027‐1034, 2004.
 433. Semb BK . Regional gastric flow changes after meal stimulation measured by the hydrogen clearance technique in conscious cats. Scand J Gastroenterol 17: 839‐842, 1982.
 434. Seth H , Axelsson M . Sympathetic, parasympathetic and enteric regulation of the gastrointestinal vasculature in rainbow trout (Oncorhynchus mykiss) under normal and postprandial conditions. J Exp Biol 214: 3118‐3126, 2010.
 435. Seth H , Grans A , Axelsson M . Cholecystokinin as a regulator of cardiac function and postprandial gastrointestinal blood flow in rainbow trout (Oncorhynchus mykiss). Am J Physiol 298: R1240‐R1248, 2010.
 436. Seth H , Sandblom E , Axelsson M . Nutrient‐induced gastrointestinal hyperemia and specific dynamic action in rainbow trout (Oncorhynchus mykiss)—Importance of proteins and lipids. Am J Physiol Regul Integr Comp Physiol 296: R345‐R352, 2009.
 437. Shafik AN . Febuxostat improves the local and remote organ changes induced by intestinal ischemia/reperfusion in rats. Dig Dis Sci 58: 650‐659, 2013.
 438. Shepherd AP . Myogenic responses of intestinal resistance and exchange vessels. Am J Physiol 233: H547‐H554, 1977.
 439. Shepherd AP . Intestinal O2 consumption and 86Rb extraction during arterial hypoxia. Am J Physiol 234: E248‐E251, 1978.
 440. Shepherd AP . Intestinal capillary blood flow during metabolic hyperemia. Am J Physiol 237: E548‐E554, 1979.
 441. Shepherd AP . Local control of intestinal oxygenation and blood flow. Annu Rev Physiol 44: 13‐27, 1982.
 442. Shepherd AP , Pawlik W , Mailman D , Burks TF , Jacobson ED . Effects of vasoconstrictors on intestinal vascular resistance and oxygen extraction. Am J Physiol 230: 298‐305, 1976.
 443. Shepherd AP , Riedel GL . Differences in reactive hyperemia between the intestinal mucosa and muscularis. Am J Physiol 247: G617‐G622, 1984.
 444. Shepherd AP , Riedel GL . Intramural distribution of intestinal blood flow during sympathetic stimulation. Am J Physiol 255: H1091‐H1095, 1988.
 445. Shepherd AP , Riedel GL . Laser‐Doppler blood flowmetry of intestinal mucosal hyperemia induced by glucose and bile. Am J Physiol 248: G393‐G397, 1985.
 446. Sherwin R , Joshi P , Hendler R , Felig P , Conn HO . Hyperglucagonemia in Laennec's cirrhosis—The role of portosystemic shunting. N Engl J Med 290: 239‐245, 1974.
 447. Shigematsu T , Specian RD , Wolf RE , Grisham MB , Granger DN . MAdCAM mediates lymphocyte‐endothelial cell adhesion in a murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol 281: G1309‐G1315, 2001.
 448. Sidky M , Bean JW . Influence of rhythmic and tonic contraction of intestinal muscle on blood flow and blood reservoir capacity in dog intestine. Am J Physiol 193: 386‐392, 1958.
 449. Sieber CC , Groszmann RJ . Nitric oxide mediates hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats. Gastroenterology 103: 235‐239, 1992.
 450. Sieber C , Sumanovski L , Moll‐Kaufmann C , Stalder G . Hyposensitivity to nerve stimulation in portal hypertensive rats: Role of nitric oxide. Eur J Clin Invest 27: 902‐907, 1997.
 451. Sikuler E , Groszmann RJ . Hemodynamic studies in long‐ and short‐term portal hypertensive cirrhosis—The relation to systemic glucagon levels. Hepatology 6: 414, 1986.
 452. Sikuler E , Groszmann RJ . Interaction of flow and resistance in maintenance of portal hypertension in a rat model. Am J Physiol 250: G205‐G212, 1986.
 453. Siregar H , Chou CC . Relative contribution of fat, protein, carbohydrate, and ethanol to intestinal hyperemia. Am J Physiol 242: G27‐G31, 1982.
 454. Sit SP , Chou CC . Time course of jejunal blood flow, O2 uptake, and O2 extraction during nutrient absorption. Am J Physiol 247: H395‐H402, 1984.
 455. Sit SP , Nyhof P , Gallavan R Jr , Chou CC . Mechanisms of glucose‐induced hyperemia in the jejunum. Proc Soc Exp Biol Med 163: 273‐277, 1980.
 456. Sitzmann JV , Campbell K , Wu Y , St. Clair C . Prostacyclin production in acute, chronic, and long‐term experimental portal hypertension. Surgery 115: 290‐294, 1994.
 457. Sjoblom M . Duodenal epithelial sensing of luminal acid: Role of carbonic anhydrases. Acta Physiol (Oxf) 201(1): 85‐95, 2011.
 458. Sjoblom‐Widfeldt N . Neuro‐muscular transmission in blood vessels: Phasic and tonic components. An in‐vitro study of mesenteric arteries of the rat. Acta Physiol Scand Suppl 587: 1‐52, 1990.
 459. Skovgaard N , Conlon JM , Wang T . Evidence that neurotensin mediates postprandial intestinal hyperemia in the python, Python regius. Am J Physiol Regul Integr Comp Physiol 293: R1393‐R1399, 2007.
 460. Slocum MM , Granger DN . Early mucosal and microvascular changes in feline intestinal transplants. Gastroenterology 105: 1761‐768, 1993.
 461. Someya N , Endo MY , Fukuba Y , Hirooka Y , Hayashi N . Effects of a mental task on splanchnic blood flow in fasting and postprandial conditions. Eur J Appl Physiol 108: 1107, 2010.
 462. Soriano A , Salas A , Salas A , Sans M , Gironella M , Elena M , Anderson DC , Piqué JM , Panés J . VCAM‐1, but not ICAM‐1 or MAdCAM‐1, immunoblockade ameliorates DSS‐induced colitis in mice. Lab Invest 80: 1541‐1551, 2000.
 463. Souza DG , Cara DC , Cassali GD , Coutinho SF , Silveira MR , Andrade SP , Poole SP , Teixeira MM . Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat. Br J Pharmacol 131: 1800‐1808, 2000.
 464. Souza DG , Lomez ES , Pinho V , Pesquero JB , Bader M , Pesquero JL , Teixeira MM . Role of bradykinin B2 and B1 receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury. J Immunol 172: 2542‐2548, 2004.
 465. Souza DG , Pinho V , Pesquero JL , Lomez ES , Poole S , Juliano L , Correa A Jr , de A Castro MS , Teixeira MM . Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury. Br J Pharmacol 139: 129‐139, 2003.
 466. Souza DG , Pinho V , Soares AC , Shimizu T , Ishii S , Teixeira MM . Role of PAF receptors during intestinal ischemia and reperfusion injury. A comparative study between PAF receptor‐deficient mice and PAF receptor antagonist treatment. Br J Pharmacol 139: 733‐740, 2003.
 467. Souza DG , Teixeira MM . The balance between the production of tumor necrosis factor‐alpha and interleukin‐10 determines tissue injury and lethality during intestinal ischemia and reperfusion. Mem Inst Oswaldo Cruz 100(Suppl 1): 59‐66, 2005.
 468. Souza DG , Vieira AT , Soares AC , Pinho V , Nicoli JR , Vieira LQ , Teixeira MM . The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J Immunol 173(6): 4137‐4146, 2004.
 469. Stebbins CL , Symons JD . Role of angiotensin II in hemodynamic responses to dynamic exercise in miniswine. J Appl Physiol 78: 185‐190, 1995.
 470. Stebbins CL , Symons JD . Vasopressin contributes to the cardiovascular response to dynamic exercise. Am J Physiol 264: H1701‐H1707, 1993.
 471. Steenbergen JM , Bohlen HG . Sodium hyperosmolarity of intestinal lymph causes arteriolar vasodilation in part mediated by EDRF. Am J Physiol 265: H323‐H328, 1993.
 472. Stevens MH , Thirlby RC , Feldman M . Mechanism for high PCO2 in gastric juice: Roles of bicarbonate secretion and CO2 diffusion. Am J Physiol 253: G527‐G530, 1987.
 473. Stokes KY , Cooper D , Tailor A , Granger DN . Hypercholesterolemia promotes inflammation and microvascular dysfunction: Role of nitric oxide and superoxide. Free Radic Biol Med 33: 1026‐1036, 2002.
 474. Sugai N , Ito S . Carbonic anhydrase, ultrastructural localization in the mouse gastric mucosa and improvements in the technique. J Histochem Cytochem 28: 511‐525, 1980.
 475. Sugamoto S , Kawauch S , Furukawa O , Mimaki TH , Takeuchi K . Role of endogenous nitric oxide and prostaglandin in duodenal bicarbonate response induced by mucosal acidification in rats. Dig Dis Sci 46(6): 1208‐1216, 2001.
 476. Sun D , Messina EJ , Kaley G , Koller A . Characteristics and origin of myogenic response in isolated mesenteric arterioles. Am J Physiol 263: H1486‐H1491, 1992.
 477. Suzuki M , Inauen W , Kvietys PR , Grisham MB , Meininger C , Schelling ME , Granger HJ , Granger DN . Superoxide mediates reperfusion‐induced leukocyte‐endothelial cell interactions. Am J Physiol 257: H1740‐H1745, 1989.
 478. Suzuki K , Sugimura K , Hasegawa K , Yoshida K , Suzuki A , Ishizuka K , Ohtsuka K , Honma T , Narisawa R , Asakura H . Activated platelets in ulcerative colitis enhance the production of reactive oxygen species by polymorphonuclear leukocytes. Scand J Gastroenterol 36: 1301‐1306, 2001.
 479. Svanes K , Varhaug JE , Holm P , Bakke A , Romslo I . Effects of hemorrhagic shock on gastric blood flow and acid secretion in cats. Acta Chir Scand 147(2): 81‐88, 1981.
 480. Svanvik J , Tyllstrom J , Wallentin I . The effects of hypercapnia and hypoxia on the distribution of capillary blood flow in the denervated intestinal vascular bed. Acta Physiol Scand 74: 543‐551, 1968.
 481. Synnerstad I , Johansson M , Nylander O , Holm L . Intraluminal acid and gastric mucosal integrity: The importance of blood‐borne bicarbonate. Am J Physiol Gastrointest Liver Physiol 280: G121‐G129, 2001.
 482. Szabó A , Boros M , Kaszaki J , Nagy S . The role of mast cells in mucosal permeability changes during ischemia‐reperfusion injury of the small intestine. Shock 8: 284‐291, 1997.
 483. Takahashi S , Takeuchi K , Okabe S . EP4 receptor mediation of prostaglandin E2‐stimulated mucus secretion by rabbit gastric epithelial cells. Biochem Pharmacol 58: 1997‐2002, 1999.
 484. Takeuchi K , Ohuchi T , Matsumoto J , Okabe S . Regulation of gastroduodenal bicarbonate secretion by capsaicin‐sensitive sensory neurons in rats. J Clin Gastroenterol 17(Suppl 1):S33‐S39, 1993.
 485. Takeuchi K , Kagawa S , Mimaki H , Aoi M , Kawauchi S . COX and NOS isoforms involved in acid‐induced duodenal bicarbonate secretion in rats. Dig Dis Sci 47: 2116‐2124, 2002.
 486. Tashima K , Nakashima M , Kagawa S , Kato S , Takeuchi K . Gastric hyperemic response induced by acid back‐diffusion in rat stomachs following barrier disruption—Relation to vanilloid type‐1 receptors. Med Sci Monit 8: BR157‐BR163, 2002.
 487. Taylor CT , Colgan SP . Hypoxia and gastrointestinal disease. J Mol Med (Berl) 85: 1295‐1300, 2007.
 488. ter Steege RWF , Kolkman JJ . Review article: The pathophysiology and management of gastrointestinal symptoms during physical exercise, and the role of splanchnic blood flow. Alimentary Pharm Therapeutics 35: 516‐528, 2012.
 489. Thomas SH , Joh T , Benoit JN . Role of bile acids in splanchnic hemodynamic response to chronic portal hypertension. Dig Dis Sci 36: 1243‐1248, 1991.
 490. Tolstanova G , Deng X , French SW , Lungo W , Paunovic B , Khomenko T , Ahluwalia A , Kaplan T , Dacosta‐Iyer M , Tarnawski A , Szabo S , Sandor Z . Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice. Lab Invest 92: 9‐21, 2012.
 491. Tolstanova G , Khomenko T , Deng X , Chen L , Tarnawski A , Ahluwalia A , Szabo S , Sandor Z . Neutralizing anti‐vascular endothelial growth factor (VEGF) antibody reduces severity of experimental ulcerative colitis in rats: Direct evidence for the pathogenic role of VEGF. J Pharmacol Exp Ther 328: 749‐757, 2009.
 492. Tzima E , Irani‐Tehrani M , Kiosses WB , Dejana E , Schultz DA , Engelhardt B , Cao G , DeLisser H , Schwartz MA . A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437: 426‐431, 2005.
 493. Valleau JD , Granger DN , Taylor AE . Effect of solute‐coupled volume absorption on oxygen consumption in cat ileum. Am J Physiol 236: E198‐E203, 1979.
 494. VanBavel E , Giezeman MJ , Mooij T , Spaan JA . Influence of pressure alterations on tone and vasomotion of isolated mesenteric small arteries of the rat. J Physiol 436: 371‐383, 1991.
 495. van Hoorn‐Hickman R , Vinik AI , van Hoorn WA . Transhepatic hormone levels in the portacaval shunted pig ‐ the effects upon gastrin and glucagon release. Am J Clin Nutr 32: 2009, 1979.
 496. Vanner S , Jiang MM , Surprenant A . Mucosal stimulation evokes vasodilation in submucosal arterioles by neuronal and nonneuronal mechanisms. Am J Physiol 264: G202, 1993.
 497. Vanner S . Mechanism of action of capsaicin on submucosal arterioles in the guinea pig ileum. Am J Physiol 265: G51‐G55, 1993.
 498. Vanner S , Macnaughton WK . Submucosal secretomotor and vasodilator reflexes. Neurogastroenterol Motil 16(Suppl 1): 39‐43, 2004.
 499. Vanner S , Surprenant A . Cholinergic and noncholinergic submucosal neurons dilate arterioles in guinea pig colon. Am J Physiol 261: G136‐G144, 1991.
 500. Vanner S , Surprenant A . Neural reflexes controlling intestinal microcirculation. Am J Physiol 271: G223‐G230, 1996.
 501. van Nieuwenhoven MA , Brouns F , Brummer RJ . Gastrointestinal profile of symptomatic athletes at rest and during physical exercise. Eur J Appl Physiol 91: 429‐434, 2004.
 502. van Nieuwenhoven MA , Vriens BE , Brummer RJ , Brouns F . Effect of dehydration on gastrointestinal function at rest and during exercise in humans. Eur J Appl Physiol 83: 578‐584, 2000.
 503. van Wijck K , Lenaerts K , Grootjans J , Wijnands KA , Poeze M , van Loon LJ , Dejong CH , Buurman WA . Physiology and pathophysiology of splanchnic hypoperfusion and intestinal injury during exercise: Strategies for evaluation and prevention. Am J Physiol Gastrointest Liver Physiol 303: G155‐G68, 2012.
 504. Varhaug JE , Svanes K , Soreide O , Skarstein A . Effect of partial gastric devascularization on mucosal blood flow and acid secretion in cats. Eur Surg Res 11: 15‐26, 1979.
 505. Varro V , Csernay L , Szarvas F , Blaho G . Effect of glucose and glycine solution on the circulation of the isolated jejunal loop in the dog. Am J Dig Dis 12: 60‐64, 1967.
 506. Vatner SF . Effects of exercise and excitement on mesenteric and renal dynamics in conscious, unrestrained baboons. Am J Physiol 234: H210‐H214, 1978.
 507. Vatner SF , Franklin D , Van Citters RL . Coronary and visceral vasoactivity associated with eating and digestion in the conscious dog. Am J Physiol 219: 1380‐1385, 1970.
 508. Vatner SF , Franklin D , Van Citters RL . Mesenteric vasoactivity associated with eating and digestion in the conscious dog. Am J Physiol 219: 170‐174, 1970.
 509. Vatner SF , Patrick TA , Higgins CB , Franklin D . Regional circulatory adjustments to eating and digestion in conscious unrestrained primates. J Appl Physiol 36: 524‐529, 1974.
 510. Victorino GP , Ramirez RM , Chong TJ , Curran B , Sadjadi J . Ischemia‐reperfusion injury in rats affects hydraulic conductivity in two phases that are temporally and mechanistically separate. Am J Physiol Heart Circ Physiol 295: H2164‐H2171, 2008.
 511. von der Weid PY , Rehal S , Ferraz JG . Role of the lymphatic system in the pathogenesis of Crohn's disease. Curr Opin Gastroenterol 27: 335‐341, 2011.
 512. Vorobioff J , Bredfeldt JE , Groszmann RJ . Hyperdynamic circulation in portal‐hypertensive rat model: A primary factor for maintenance of chronic portal hypertension. Am J Physiol 244: G52‐G57, 1983.
 513. Vowinkel T , Anthoni C , Wood KC , Stokes KY , Russell J , Gray L , Bharwani S , Senninger N , Alexander JS , Krieglstein CF , Grisham MB , Granger DN . CD40‐CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon. Gastroenterology 132: 955‐965, 2007.
 514. Vowinkel T . Granger DN . Gastrointestinal blood flow. In: Yamada T , editor. Textbook of Gastroenterology (6th ed). Wiley‐Blackwell, 2015.
 515. Vowinkel T , Wood KC , Stokes KY , Russell J , Tailor A , Anthoni C , Senninger N , Krieglstein CF , Granger DN . Mechanisms of platelet and leukocyte recruitment in experimental colitis. Am J Physiol Gastrointest Liver Physiol 293: G1054‐G1060, 2007.
 516. Walder CE , Thiemermann C , Vane JR . Endothelium‐derived relaxing factor participates in the increased blood flow in response to pentagastrin in the rat stomach mucosa. Proc Biol Sci 241: 195‐200, 1990.
 517. Wallace JL , McKnight GW . The mucoid cap over superficial gastric damage in the rat. A high‐pH microenvironment dissipated by nonsteroidal antiinflammatory drugs and endothelin. Gastroenterology 99: 295‐304, 1990.
 518. Walter U , Gambaryan S . cGMP and cGMP‐dependent protein kinase in platelets and blood cells. Handb Exp Pharmacol 191: 533‐548, 2009.
 519. Walus KM , Fondacaro JD , Jacobson ED . Hemodynamic and metabolic changes during stimulation of ileal motility. Dig Dis Sci 26: 1069‐1077, 1981.
 520. Waterman JJ , Kapur R . Upper gastrointestinal issues in athletes. Curr Sports Med Rep 11:99‐104, 2012.
 521. Weber C , Fraemohs L , Dejana E . The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7(6): 467‐477, 2007.
 522. Weinbaum S , Tarbell JM , Damiano ER . The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9: 121‐167, 2007.
 523. Weiss SJ . Tissue destruction by neutrophils. N Engl J Med 320: 365, 1989.
 524. Weitzberg E , Hezel M , Lundberg JO . Nitrate‐nitrite‐nitric oxide pathway: Implications for anesthesiology and intensive care. Anesthesiology 113: 1460‐1475, 2010.
 525. Wheaton LG , Sarr MG , Schlossberg L , Bulkley GB . Gross anatomy of the splanchnic vasculature. In: Granger DN , Bulkley GB , editors. Measurement of Blood Flow: Applicatios to the Splanchnic Circulation. Baltimore: Williams & Wilkins, 1981, pp. 9‐45.
 526. Whipple AO . The problem of portal hypertension in relation to the hepatosplenopathies. Ann Surg 122: 449‐475, 1945.
 527. Wiest R , Groszmann RJ . The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough. Hepatology 35: 478‐491, 2002.
 528. Wiest R , Shah V , Sessa WC , et al. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol 276: G1043‐G1051, 1999.
 529. Williams SE , Turnberg LA . Demonstration of a pH gradient across mucus adherent to rabbit gastric mucosa: Evidence for a ‘mucus‐bicarbonate’ barrier. Gut 22:94‐96, 1981.
 530. Witte CL , Witte MH . Splanchnic circulatory and tissue fluid dynamics in portal hypertension. Fed Proc 42: 1685‐1689, 1983.
 531. Wood JG , Wicina GM , Cheung LY . Effects of histamine and 1, 4‐methylhistamine on gastric vascular resistance in dogs. Am J Physiol 258: G440‐G446, 1990.
 532. Wu Y , Burns RC , Sitzmann JV . Effects of nitric oxide and cyclooxygenase inhibition on splanchnic hemodynamics in portal hypertension. Hepatology 18: 1416‐1421, 1993.
 533. Xiang L , Hester RL . Cardiovascular responses to exercise. In: Granger DN , Granger JP , editors. Integrated Systems Physiology: From Molecule to Function. San Rafael (CA): Morgan & Claypool Life Sciences, 2012, pp. 1‐124.
 534. Xie H , Ray PE , Short BL . Role of sensory C fibers in hypoxia/reoxygenation‐impaired myogenic constriction of cerebral arteries. Neurol Res 32: 487‐491, 2010.
 535. Xu L , Carter EP , Ohara M , et al. Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis. Am J Physiol Renal Physiol 279: F1110‐F1115, 2000.
 536. Yamamoto S , Tanabe M , Wakabayashi G , Shimazu M , Matsumoto K , Kitajima M . The role of tumor necrosis factor‐alpha and interleukin‐1beta in ischemia‐reperfusion injury of the rat small intestine. J Surg Res 99: 134‐41, 2001.
 537. Yang H , Jin Y , Li M , Wang CH , Tang CW . Disturbances of mesenteric lymph flow and in vivo intestinal lymphocyte trafficking during early gut injury induced by ischemia‐reperfusion in rats. Lymphology 45: 130‐139, 2012.
 538. Yang Q , Zheng FP , Zhan YS , Tao J , Tan SW , Liu HL , Wu B . Tumor necrosis factor‐α mediates JNK activation response to intestinal ischemia‐reperfusion injury. World J Gastroenterol 19: 4925‐4934, 2013.
 539. Yoshida N , Granger DN , Anderson DC , Rothlein R , Lane C , Kvietys PR . Anoxia/reoxygenation‐induced neutrophil adherence to cultured endothelial cells. Am J Physiol 262: H1891, 1992.
 540. Yryle LF , Smith JK , Benoit JN , Granger DN , Korthuis RJ . Role of glucagon in intestinal hyperemia associated with early experimental diabetes mellitus. Am J Physiol 255: G542‐G546, 1988.
 541. Yuan SY . Signal transduction pathways in enhanced microvascular permeability. Microcirculation 7: 395‐403, 2000.
 542. Zampell JC , Aschen S , Weitman ES , Yan A , Elhadad S , DeBrot M , Mehrara BJ . Regulation of adipogenesis by lymphatic fluid stasis: Part I. Adipogenesis, fibrosis, and inflammation. Plast Reconstr Surg 129: 825‐834, 2012.
 543. Zani BG , Bohlen HG . Sodium channels are required during In vivo sodium chloride hyperosmolarity to stimulate increase in intestinal endothelial nitric oxide production. Am J Physiol Heart Circ Physiol 288: H89‐H95, 2005.
 544. Zani BG , Bohlen HG . Transport of extracellular l‐arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production. Am J Physiol Heart Circ Physiol 28: H1381‐H1390, 2005.
 545. Zhang XW , Liu Q , Thorlacius H . Inhibition of selectin function and leukocyte rolling protects against dextran sodium sulfate‐induced murine colitis. Scand J Gastroenterol 36: 270‐275, 2001.
 546. Zimmerman BJ , Grisham MB , Granger DN . Role of oxidants in ischemia/reperfusion‐induced granulocyte infiltration. Am J Physiol 258: G185‐G190, 1990.
 547. Zimmerman BJ , Guillory DJ , Grisham MB , Gaginella TS , Granger DN . Role of leukotriene B4 in granulocyte infiltration into the postischemic feline intestine. Gastroenterology 99: 1358‐1363, 1990.

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Article Title: The Gastrointestinal Circulation: Physiology and Pathophysiology
 

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D. Neil Granger, Lena Holm, Peter Kvietys. The Gastrointestinal Circulation: Physiology and Pathophysiology. Compr Physiol 2015, 5: 1541-1583. doi: 10.1002/cphy.c150007