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The Gastrointestinal Circulation: Physiology and Pathophysiology

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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 ().
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 ().
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 ().
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 ().
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 ().
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 ().
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 () and Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 ().
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 ().
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 ().]
Figure 10. Figure 10. Relationship between oxygen uptake and blood flow (oxygen delivery). The curves depicted represent a composite of those shown in Figure . 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 ().
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 ().
Figure 12. Figure 12. Intestinal blood flow response following luminal placement of different specific constituents of chyme. Modified, with permission, from Granger et al. ().
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 ().
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. ().
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 ().
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 ().
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 ().
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 ().
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 ()]. 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 ().
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 ().
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 () (panel A) and Mori et al. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005 () (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 () (panels A‐D) and Chidlow et al. Am J Pathol 169: 2014‐2030, 2006 () (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. and ). 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 ().]


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 ().


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 ().


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 ().


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 ().


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 ().


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 ().


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 () and Granger, Kvietys, Korthuis, and Premen. Comp Physiol 1405‐1474, 2011 ().


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 ().


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 ().]


Figure 10. Relationship between oxygen uptake and blood flow (oxygen delivery). The curves depicted represent a composite of those shown in Figure . 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 ().


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 ().


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


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 ().


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. ().


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 ().


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 ().


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 ().


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 ().


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 ()]. 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 ().


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 ().


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 () (panel A) and Mori et al. Am J Physiol Gastrointest Liver Physiol 289: G1024‐G1029, 2005 () (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 () (panels A‐D) and Chidlow et al. Am J Pathol 169: 2014‐2030, 2006 () (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. and ). 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 ().]
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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