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Nitric Oxide and the Cardiovascular System

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ABSTRACT

Nitric oxide (NO) generated by endothelial cells to relax vascular smooth muscle is one of the most intensely studied molecules in the past 25 years. Much of what is known about NO regulation of NO is based on blockade of its generation and analysis of changes in vascular regulation. This approach has been useful to demonstrate the importance of NO in large scale forms of regulation but provides less information on the nuances of NO regulation. However, there is a growing body of studies on multiple types of in vivo measurement of NO in normal and pathological conditions. This discussion will focus on in vivo studies and how they are reshaping the understanding of NO's role in vascular resistance regulation and the pathologies of hypertension and diabetes mellitus. The role of microelectrode measurements in the measurement of [NO] will be considered because much of the controversy about what NO does and at what concentration depends upon the measurement methodology. For those studies where the technology has been tested and found to be well founded, the concept evolving is that the stresses imposed on the vasculature in the form of flow‐mediated stimulation, chemicals within the tissue, and oxygen tension can cause rapid and large changes in the NO concentration to affect vascular regulation. All these functions are compromised in both animal and human forms of hypertension and diabetes mellitus due to altered regulation of endothelial cells and formation of oxidants that both damage endothelial cells and change the regulation of endothelial nitric oxide synthase. © 2015 American Physiological Society. Compr Physiol 5:803‐828, 2015.

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Figure 1. Figure 1. (Panel A) Blood flow in an intestinal arteriole was increased by occlusion of parallel arterioles as [NO] was measured on the surface of the arteriole. The data at 3‐s intervals (mean data straight lines) demonstrate a rapid increase in [NO] with increased flow and an equally rapid decline in [NO] when flow was returned to normal. Spikes represent artifacts of tissue movement which bend the microelectrode. (Panel B) A downstream section of an arteriole was occluded to rapidly lower flow and the mean [NO] decreased quickly. Upon release of the occlusion, flow increased to normal and [NO] was elevated. Adapted, with permission, from Figure 4 of ().
Figure 2. Figure 2. In Panels A and B, an open tip 7‐μm‐diameter carbon fiber microelectrode approached the surface of 2‐mm metallic disk NO electrode: a similar process was done to 30‐μm diameter by 2‐mm‐long carbon fiber WPI electrodes in Panel C and D in the presence of NO solution flowing through a tissue chamber. As the larger electrodes were approached in each panel, the NO current of the 7‐μm‐diameter carbon fiber microelectrode decreased as the electrode tip entered the unstirred layer about the larger electrode and NO within this layer had been consumed. The [NO] reported by larger electrodes was not shown because it did not change. Withdrawal of the open tip 7‐μm microelectrode resulted in an increased [NO] at about 50 μm from the 2‐mm WPI electrodes and at about 10 μm for 30 μm WPI electrodes, indicating the approximate distance of influence of the unstirred layer effects. When 7‐ and 10‐μm microelectrodes were approached, the current of the exploring microelectrode did not change, indicating a minimal unstirred layer and diffusion interaction. Adapted, with permission, from Figure 4 of ().
Figure 3. Figure 3. Arteriolar inner diameter and perivascular [NO] were measured as either small volumes of 1200 nmol/L NO gas equilibrated solution or GSNO was added to the incoming bathing media over an in vivo intestinal preparation. The dilation to a given [NO] caused by either source of NO caused comparable dilation. After exposure of NO and the resulting dilation, when the NO source was removed, there was a rebound constriction and reduction in [NO] for both NO sources. With elevated or reduced [NO] from either source, the changes in diameter were equivalent, with similar regression statistics shown in the figure. Adapted, with permission, from Figure 6 of ().
Figure 4. Figure 4. The relationships of [NO] to red blood cell velocity and shear rate for large (1A) and intermediate diameter (2A) in vivo intestinal arterioles as both were altered by either occlusion of a parallel arteriole or downstream occlusion of the arteriole studied. The change in [NO] was approximately linear for the range of velocity and shear rate studied and on a relative basis, about 1.3× larger for 1A than 2A. The linear regression equations were Velocity: 1A, 0.85× + 20.8, r2 = 0.53, P < 0.05; 2A, 0.52× + 50.7, r2 = 0.58. Shear rate: 1A, 0.75× + 33.6, r2 = 0.53, P < 0.05; 2A, 0.59× + 45.2, r2 = 0.56, P < 0.05. Adapted, with permission, from Figure 9 of ().
Figure 5. Figure 5. The upper panel is a long‐term [NO] recording along a valve structure of an in vivo rat mesenteric lymphatic before and after the animal was given intravenous saline to increase lymph production. The vertical gray marks are contractions. The vessel wall [NO] increased along with the frequency of contractions over a 30‐min period. In the lower panel, the [NO] of a valve area and a downstream tubular area after saline infusion are shown: these are not simultaneous recordings but were recorded within about 10 min of each other. The valvular areas consistently have a higher [NO] than nearby tubular areas under all conditions. The higher frequency variations of NO are artifacts of mechanical ventilation moving the tissue preparation. The gray marks signal the start of contraction and within 1 to 2 s thereafter, the local [NO] began to rise. Adapted, with permission, from Figure 2 of ().
Figure 6. Figure 6. Paired measurements of in vivo rat mesenteric lymphatic valve and tubular areas along with nearby (20‐30 μm) adipose tissue and 500‐μm distant in adipose tissue. The purpose of the measurements is to demonstrate that mesenteric tissue does have a background [NO] that under resting conditions is similar to the [NO] along tubular sections of the lymphatic. The tubular section [NO] did increase with flow stimulation as shown in Figure 5. The data were obtained for 12 lymphatics of 10 rats. The valve bulb area has a consistently high [NO] whereas the tubular region has a [NO] similar to that in tissue. However, both regions of the lymphatic can increase [NO] during increased contractions. Adapted, with permission, from Figure 3 of ().
Figure 7. Figure 7. Panel A presents the expression of eNOS measured by immunofluorescence histochemistry of isolated rat mesenteric lymphatic vessels using confocal microscopy. The left of panel A is a reconstruction of the three‐dimensional view of a lymphatic vessel showing the valvular, sinus, valve leaflets, and tubular regions. The intensity of fluorescence is shown on the right side of panel A for 18 vessels with 100% relative intensity at a point as the valvular leaflet insert. The greatest intensity, eNOS expression, occurs in the valve bulb region and tapers off down the tubular region. Panel B is a reconstruction of the center one‐fourth of the vessel to illustrate intensity of the wall of specific structures. The intensity data was color coded with hotter colors as greater intensity or expression relative to the valve insertion point area. The averaged data for six vessels on the left side of panel B show the highest expression in the valve wall and valve leaflet mid points. Adapted, with permission, from Figure 4 from ().
Figure 8. Figure 8. L‐Lysine was used to compete for transport against l‐arginine by the CAT‐1 transporter and in doing so, suppress eNOS formation of NO. Panel A for blood flow and Panel B for relative [NO] demonstrated that reduction in in vivo oxygen tension by lowering the bath oxygen percentage from 5% to 0% for intestinal arterioles increased blood flow and [NO]. During l‐lysine exposure, flow and [NO] decreased at rest and neither responded appropriately to decreased oxygen tension. Data are means ± SE. *, P < 0.05 versus the control; #, P < 0.05 versus the natural paired condition. Adapted, with permission, from original Figure 7 of ().
Figure 9. Figure 9. A proposed scheme for NO generation by vascular endothelial cells during NaCl hyperosmolarity at point A and reduced oxygen tension at point C with both acting through the Na+/K+/2Cl cotransporter followed by removal of sodium in exchange for calcium by the Na+/Ca2+ exchanger (NCX). At B, increased flow shear increases calcium entry to activate eNOS. In all three scenarios, entry of l‐arginine through the CAT‐1 transporter is required to support the increased NO production, all of which fail if l‐lysine is used to compete for transport. Adapted, with permission, from original Figure 7 of ().
Figure 10. Figure 10. The data in panel A are in vivo cerebral periarteriolar [NO] responses and panel B is diameter responses to a decrease in cerebral oxygen availability before and after nNOS was blocked. Oxygen availability was reduced by lowering the bath oxygen tension. The nNOS blockade both caused constriction and reduced [NO], likely reflecting the loss of the NO generated by nNOS in normal conditions. The nNOS blockade eliminated both the dilation and increased [NO] to reduced oxygen availability. Tests of eNOS function during nNOS blockade demonstrated it was functional (). The data are based on six rats and * indicates statistical significance from control and, # is a significant difference from normal conditions at low oxygen tension. Adapted, with permission, from Figure 8 of ().
Figure 11. Figure 11. In Zucker obese rats prior to developing transient hyperglycemia, lowering the local intestinal vascular oxygen tension caused significantly less increased blood flow and elevated [NO] than in normal lean Zucker rats. After blockade of PKC β‐11, lean animals were unaffected but obese animals experience increased blood flow at rest and during decreased oxygen availability. These data indicate PKC activation in obese animals limits NO physiology both at rest and when called upon to increase NO production at reduced oxygen tension. The data are based on five obese and six lean Zucker rats. An asterisk represents a significant event from 5% to 0% oxygen and two asterisks indicate a significant change after PKC blockade. Adapted, with permission, from Figure 1 of (27).
Figure 12. Figure 12. The percent of control changes in intestinal blood flow in panel A and perivascular [NO] in panel B as blood flow was increased by occlusion of parallel arterioles and decreased by downstream occlusion of the arteriole of interest. Both of these variables were suppressed in obese Zucker rats relative to responses in lean rats and these deficits were essentially restored to normal after acute blockade of PKC‐βII. The data were obtained in seven obese and lean Zucker rats, one arteriole per animal. A single asterisk represents significant change within a rat type and two asterisks indicate a change with drug blockade. Adapted, with permission, from Figure 2 of ().
Figure 13. Figure 13. The resting [NO] and diameter of large intestinal arterioles in obese, nonhyperglycemic Zucker rats was lower than normal in age matched lean animals. Both groups had suppressed NO function to topical acute 300 mg/dL hyperglycemia but 200 mg/dL d‐glucose in obese rats caused as much compromise as 300 mg/dL in lean rats. The lean rats were insensitive to 200 mg/dL d‐glucose for 1 h with a small deficit at 2 h of exposure. After the hyperglycemia of one hour duration was stopped, recovery was not evident in neither lean nor obese rats for at least two hours. Twelve normal vessels from 6 lean rats and 12 vessels from obese animals were studied. *Significant change during hyperglycemia relative to control. Adapted, with permission, from Figure 3 of ().


Figure 1. (Panel A) Blood flow in an intestinal arteriole was increased by occlusion of parallel arterioles as [NO] was measured on the surface of the arteriole. The data at 3‐s intervals (mean data straight lines) demonstrate a rapid increase in [NO] with increased flow and an equally rapid decline in [NO] when flow was returned to normal. Spikes represent artifacts of tissue movement which bend the microelectrode. (Panel B) A downstream section of an arteriole was occluded to rapidly lower flow and the mean [NO] decreased quickly. Upon release of the occlusion, flow increased to normal and [NO] was elevated. Adapted, with permission, from Figure 4 of ().


Figure 2. In Panels A and B, an open tip 7‐μm‐diameter carbon fiber microelectrode approached the surface of 2‐mm metallic disk NO electrode: a similar process was done to 30‐μm diameter by 2‐mm‐long carbon fiber WPI electrodes in Panel C and D in the presence of NO solution flowing through a tissue chamber. As the larger electrodes were approached in each panel, the NO current of the 7‐μm‐diameter carbon fiber microelectrode decreased as the electrode tip entered the unstirred layer about the larger electrode and NO within this layer had been consumed. The [NO] reported by larger electrodes was not shown because it did not change. Withdrawal of the open tip 7‐μm microelectrode resulted in an increased [NO] at about 50 μm from the 2‐mm WPI electrodes and at about 10 μm for 30 μm WPI electrodes, indicating the approximate distance of influence of the unstirred layer effects. When 7‐ and 10‐μm microelectrodes were approached, the current of the exploring microelectrode did not change, indicating a minimal unstirred layer and diffusion interaction. Adapted, with permission, from Figure 4 of ().


Figure 3. Arteriolar inner diameter and perivascular [NO] were measured as either small volumes of 1200 nmol/L NO gas equilibrated solution or GSNO was added to the incoming bathing media over an in vivo intestinal preparation. The dilation to a given [NO] caused by either source of NO caused comparable dilation. After exposure of NO and the resulting dilation, when the NO source was removed, there was a rebound constriction and reduction in [NO] for both NO sources. With elevated or reduced [NO] from either source, the changes in diameter were equivalent, with similar regression statistics shown in the figure. Adapted, with permission, from Figure 6 of ().


Figure 4. The relationships of [NO] to red blood cell velocity and shear rate for large (1A) and intermediate diameter (2A) in vivo intestinal arterioles as both were altered by either occlusion of a parallel arteriole or downstream occlusion of the arteriole studied. The change in [NO] was approximately linear for the range of velocity and shear rate studied and on a relative basis, about 1.3× larger for 1A than 2A. The linear regression equations were Velocity: 1A, 0.85× + 20.8, r2 = 0.53, P < 0.05; 2A, 0.52× + 50.7, r2 = 0.58. Shear rate: 1A, 0.75× + 33.6, r2 = 0.53, P < 0.05; 2A, 0.59× + 45.2, r2 = 0.56, P < 0.05. Adapted, with permission, from Figure 9 of ().


Figure 5. The upper panel is a long‐term [NO] recording along a valve structure of an in vivo rat mesenteric lymphatic before and after the animal was given intravenous saline to increase lymph production. The vertical gray marks are contractions. The vessel wall [NO] increased along with the frequency of contractions over a 30‐min period. In the lower panel, the [NO] of a valve area and a downstream tubular area after saline infusion are shown: these are not simultaneous recordings but were recorded within about 10 min of each other. The valvular areas consistently have a higher [NO] than nearby tubular areas under all conditions. The higher frequency variations of NO are artifacts of mechanical ventilation moving the tissue preparation. The gray marks signal the start of contraction and within 1 to 2 s thereafter, the local [NO] began to rise. Adapted, with permission, from Figure 2 of ().


Figure 6. Paired measurements of in vivo rat mesenteric lymphatic valve and tubular areas along with nearby (20‐30 μm) adipose tissue and 500‐μm distant in adipose tissue. The purpose of the measurements is to demonstrate that mesenteric tissue does have a background [NO] that under resting conditions is similar to the [NO] along tubular sections of the lymphatic. The tubular section [NO] did increase with flow stimulation as shown in Figure 5. The data were obtained for 12 lymphatics of 10 rats. The valve bulb area has a consistently high [NO] whereas the tubular region has a [NO] similar to that in tissue. However, both regions of the lymphatic can increase [NO] during increased contractions. Adapted, with permission, from Figure 3 of ().


Figure 7. Panel A presents the expression of eNOS measured by immunofluorescence histochemistry of isolated rat mesenteric lymphatic vessels using confocal microscopy. The left of panel A is a reconstruction of the three‐dimensional view of a lymphatic vessel showing the valvular, sinus, valve leaflets, and tubular regions. The intensity of fluorescence is shown on the right side of panel A for 18 vessels with 100% relative intensity at a point as the valvular leaflet insert. The greatest intensity, eNOS expression, occurs in the valve bulb region and tapers off down the tubular region. Panel B is a reconstruction of the center one‐fourth of the vessel to illustrate intensity of the wall of specific structures. The intensity data was color coded with hotter colors as greater intensity or expression relative to the valve insertion point area. The averaged data for six vessels on the left side of panel B show the highest expression in the valve wall and valve leaflet mid points. Adapted, with permission, from Figure 4 from ().


Figure 8. L‐Lysine was used to compete for transport against l‐arginine by the CAT‐1 transporter and in doing so, suppress eNOS formation of NO. Panel A for blood flow and Panel B for relative [NO] demonstrated that reduction in in vivo oxygen tension by lowering the bath oxygen percentage from 5% to 0% for intestinal arterioles increased blood flow and [NO]. During l‐lysine exposure, flow and [NO] decreased at rest and neither responded appropriately to decreased oxygen tension. Data are means ± SE. *, P < 0.05 versus the control; #, P < 0.05 versus the natural paired condition. Adapted, with permission, from original Figure 7 of ().


Figure 9. A proposed scheme for NO generation by vascular endothelial cells during NaCl hyperosmolarity at point A and reduced oxygen tension at point C with both acting through the Na+/K+/2Cl cotransporter followed by removal of sodium in exchange for calcium by the Na+/Ca2+ exchanger (NCX). At B, increased flow shear increases calcium entry to activate eNOS. In all three scenarios, entry of l‐arginine through the CAT‐1 transporter is required to support the increased NO production, all of which fail if l‐lysine is used to compete for transport. Adapted, with permission, from original Figure 7 of ().


Figure 10. The data in panel A are in vivo cerebral periarteriolar [NO] responses and panel B is diameter responses to a decrease in cerebral oxygen availability before and after nNOS was blocked. Oxygen availability was reduced by lowering the bath oxygen tension. The nNOS blockade both caused constriction and reduced [NO], likely reflecting the loss of the NO generated by nNOS in normal conditions. The nNOS blockade eliminated both the dilation and increased [NO] to reduced oxygen availability. Tests of eNOS function during nNOS blockade demonstrated it was functional (). The data are based on six rats and * indicates statistical significance from control and, # is a significant difference from normal conditions at low oxygen tension. Adapted, with permission, from Figure 8 of ().


Figure 11. In Zucker obese rats prior to developing transient hyperglycemia, lowering the local intestinal vascular oxygen tension caused significantly less increased blood flow and elevated [NO] than in normal lean Zucker rats. After blockade of PKC β‐11, lean animals were unaffected but obese animals experience increased blood flow at rest and during decreased oxygen availability. These data indicate PKC activation in obese animals limits NO physiology both at rest and when called upon to increase NO production at reduced oxygen tension. The data are based on five obese and six lean Zucker rats. An asterisk represents a significant event from 5% to 0% oxygen and two asterisks indicate a significant change after PKC blockade. Adapted, with permission, from Figure 1 of (27).


Figure 12. The percent of control changes in intestinal blood flow in panel A and perivascular [NO] in panel B as blood flow was increased by occlusion of parallel arterioles and decreased by downstream occlusion of the arteriole of interest. Both of these variables were suppressed in obese Zucker rats relative to responses in lean rats and these deficits were essentially restored to normal after acute blockade of PKC‐βII. The data were obtained in seven obese and lean Zucker rats, one arteriole per animal. A single asterisk represents significant change within a rat type and two asterisks indicate a change with drug blockade. Adapted, with permission, from Figure 2 of ().


Figure 13. The resting [NO] and diameter of large intestinal arterioles in obese, nonhyperglycemic Zucker rats was lower than normal in age matched lean animals. Both groups had suppressed NO function to topical acute 300 mg/dL hyperglycemia but 200 mg/dL d‐glucose in obese rats caused as much compromise as 300 mg/dL in lean rats. The lean rats were insensitive to 200 mg/dL d‐glucose for 1 h with a small deficit at 2 h of exposure. After the hyperglycemia of one hour duration was stopped, recovery was not evident in neither lean nor obese rats for at least two hours. Twelve normal vessels from 6 lean rats and 12 vessels from obese animals were studied. *Significant change during hyperglycemia relative to control. Adapted, with permission, from Figure 3 of ().
References
 1.Abu El‐Asrar AM. Evolving strategies in the management of diabetic retinopathy. Middle East Afr J Ophthalmol 20: 273‐282, 2013.
 2.Aggoun Y, Szezepanski I, Bonnet D. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children. Pediatr Res 58: 173‐178, 2005.
 3.Alef MJ, Vallabhaneni R, Carchman E, Morris SM, Jr., Shiva S, Wang Y, Kelley EE, Tarpey MM, Gladwin MT, Tzeng E, Zuckerbraun BS. Nitrite‐generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague‐Dawley rats. J Clin Invest 121: 1646‐1656, 2011.
 4.Allen BW, Liu J, Piantadosi CA. Electrochemical detection of nitric oxide in biological fluids. Methods Enzymol 396: 68‐77, 2005.
 5.Armas‐Padilla MC, Armas‐Hernandez MJ, Sosa‐Canache B, Cammarata R, Pacheco B, Guerrero J, Carvajal AR, Hernandez‐Hernandez R, Israili ZH, Valasco M. Nitric oxide and malondialdehyde in human hypertension. Am J Ther 14: 172‐176, 2007.
 6.Armstead WM. Opioids and nitric oxide contribute to hypoxia‐induced pial arterial vasodilation in newborn pigs. Am J Physiol 268: H226‐H232, 1995.
 7.Aroor AR, Demarco VG, Jia G, Sun Z, Nistala R, Meininger GA, Sowers JR. The role of tissue Renin‐Angiotensin‐aldosterone system in the development of endothelial dysfunction and arterial stiffness. Front Endocrinol (Lausanne) 4: 161, 2013.
 8.Arrick DM, Sharpe GM, Sun H, Mayhan WG. nNOS‐dependent reactivity of cerebral arterioles in Type 1 diabetes. Brain Res 1184: 365‐371, 2007.
 9.Bansal D, Badhan Y, Gudala K, Schifano F. Ruboxistaurin for the treatment of diabetic peripheral neuropathy: A systematic review of randomized clinical trials. Diabetes Metab J 37: 375‐384, 2013.
 10.Barbosa VA, Luciano TF, Marques SO, Vitto MF, Souza DR, Silva LA, Santos JP, Moreira JC, Dal‐Pizzol F, Lira FS, Pinho RA, De Souza CT. Acute exercise induce endothelial nitric oxide synthase phosphorylation via Akt and AMP‐activated protein kinase in aorta of rats: Role of reactive oxygen species. Int J Cardiol 167: 2983‐2988, 2013.
 11.Baron AD. Cardiovascular actions of insulin in humans. Implications for insulin sensitivity and vascular tone. Baillier's Clin Endo Metab 7: 961‐987, 1996.
 12.Baron AD. The coupling of glucose metabolism and perfusion in human skeletal muscle: The potential role of endothelium‐derived nitric oxide. Diabetes 45: S105‐S109, 1996.
 13.Baron AD, Brechtel G, Johnson A, Fineberg N, Henry DP, Steinberg HO. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity: Studies in lean and obese men. J Clin Invest 93: 2453‐2462, 1994.
 14.Barron LA, Green GM, Khalil RA. Gender differences in vascular smooth muscle reactivity to increases in extracellular sodium salt. Hypertension 39: 425‐432, 2002.
 15.Bauser‐Heaton HD, Bohlen HG. Cerebral microvascular dilation during hypotension and decreased oxygen tension: A role for nNOS. Am J Physiol Heart Circ Physiol 293: H2193‐H2201, 2007.
 16.Bauser‐Heaton HD, Song J, Bohlen HG. Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide‐sensitive cotransporter and sodium‐calcium exchanger. Am J Physiol Heart Circ Physiol 294: H2166‐H2173, 2008.
 17.Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase Cbeta prevents impaired endothelium‐dependent vasodilation caused by hyperglycemia in humans. Circ Res 90: 107‐111, 2002.
 18.Beckman JA, Paneni F, Cosentino F, Creager MA. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part II. Eur Heart J 34: 2444‐2452, 2013.
 19.Benarroch EE. Brain glucose transporters: Implications for neurologic disease. Neurology 82: 1374‐1379, 2014.
 20.Benoit JN, Zawieja DC, Goodman AH, Granger HJ. Characterization of intact mesenteric lymphatic pump and its responsiveness to acute edemagenic stress. Am J Physiol 257: H2059‐H2069, 1989.
 21.Bernatchez PN, Bauer PM, Yu J, Prendergast JS, He P, Sessa WC. Dissecting the molecular control of endothelial NO synthase by caveolin‐1 using cell‐permeable peptides. Proc Natl Acad Sci U S A 102: 761‐766, 2005.
 22.Bernatova I. Endothelial dysfunction in experimental models of arterial hypertension: Cause or consequence?. Biomed Res Int 2014: 598271, 2014.
 23.Bevan JA, Joyce EH. Flow‐dependent dilation in myograph‐mounted resistance artery segments. Blood Vessels 25: 101‐104, 1988.
 24.Bevan JA, Joyce EH, Wellman GC. Flow‐dependent dilation in a resistance artery still occurs after endothelium removal. Circ Res 63: 980‐985, 1988.
 25.Bode‐Boger SM, Boger RH, Kielstein JT, Loffler M, Schaffer J, Frolich JC. Role of endogenous nitric oxide in circadian blood pressure regulation in healthy humans and in patients with hypertension or atherosclerosis. J Investig Med 48: 125‐132, 2000.
 26.Bohlen HG. Mechanism of increased vessel wall nitric oxide concentrations during intestinal absorption. Am J Physiol 275: H542‐H550, 1998.
 27.Bohlen HG. Protein kinase betaII in Zucker obese rats compromises oxygen and flow‐mediated regulation of nitric oxide formation. Am J Physiol Heart Circ Physiol 286: H492‐H497, 2004.
 28.Bohlen HG. Is the real in vivo nitric oxide concentration pico or nano molar? Influence of electrode size on unstirred layers and NO consumption. Microcirculation 20: 30‐41, 2013.
 29.Bohlen HG, Gasheva OY, Zawieja DC. Nitric oxide formation by lymphatic bulb and valves is a major regulatory component of lymphatic pumping. Am J Physiol Heart Circ Physiol 301: H1897‐H1906, 2011.
 30.Bohlen HG, Lash JM. Intestinal lymphatic vessels release endothelial‐dependent vasodilators. Am J Physiol 262: H813‐H819, 1992.
 31.Bohlen HG, Lash JM. Topical hyperglycemia rapidly suppresses EDRF‐mediated vasodilation of normal rat arterioles. Am J Physiol 265: H219‐H225, 1993.
 32.Bohlen HG, Lash JM. Intestinal absorption of sodium and nitric oxide‐dependent vasodilation interact to dominate resting vascular resistance. Circ Res 78: 231‐237, 1996.
 33.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.
 34.Bohlen HG, Nase GP. Arteriolar nitric oxide concentration is decreased during hyperglycemia‐induced betaII PKC activation. Am J Physiol Heart Circ Physiol 280: H621‐H627, 2001.
 35.Bohlen HG, Nase GP. Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function. Am J Physiol Heart Circ Physiol 283: H391‐H397, 2002.
 36.Bohlen HG, Nase GP, Jin JS. Multiple mechanisms of early hyperglycaemic injury of the rat intestinal microcirculation. Clin Exp Pharmacol Physiol 29: 138‐142, 2002.
 37.Bohlen HG, Wang W, Gashev A, Gasheva O, Zawieja D. Phasic contractions of rat mesenteric lymphatics increase basal and phasic nitric oxide generation in vivo. Am J Physiol Heart Circ Physiol 297: H1319‐H1328, 2009.
 38.Bohlen HG, Zhou X, Unthank JL, Miller SJ, Bills R. Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation. Am J Physiol Heart Circ Physiol 297: H1337‐H1346, 2009.
 39.Bottaro DP, Bonner‐Weir S, King GL. Insulin receptor recycling in vascular endothelial cells: Regulation by insulin and phorbol ester. 264: 5916‐5923, 1989.
 40.Breton‐Romero R, Gonzalez de OC, Romero N, Sanchez‐Gomez FJ, de AC, Porras A, Rodriguez‐Pascual F, Laranjinha J, Radi R, Lamas S. Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress. Free Radic Biol Med 52: 1093‐1100, 2012.
 41.Bueno M, Wang J, Mora AL, Gladwin MT. Nitrite signaling in pulmonary hypertension: Mechanisms of bioactivation, signaling, and therapeutics. Antioxid Redox Signal 18: 1797‐1809, 2013.
 42.Buerk DG. Can we model nitric oxide biotransport? A survey of mathematical models for a simple diatomic molecule with surprisingly complex biological activities. Annu Rev Biomed Eng 3: 109‐143, 2001.
 43.Buerk DG. Mathematical modeling of the interaction between oxygen, nitric oxide and superoxide. Adv Exp Med Biol 645: 7‐12, 2009.
 44.Buerk DG, Ances BM, Greenberg JH, Detre JA. Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 18: 1‐9, 2003.
 45.Buerk DG, Atochin DN, Riva CE. Simultaneous tissue PO2, nitric oxide, and laser Doppler blood flow measurements during neuronal activation of optic nerve. Adv Exp Med Biol 454: 159‐164, 1998.
 46.Buerk DG, Atochin DN, Riva CE. Investigating the role of nitric oxide in regulating blood flow and oxygen delivery from in vivo electrochemical measurements in eye and brain. Adv Exp Med Biol 530: 359‐370, 2003.
 47.Buerk DG, Barbee KA, Jaron D. Modeling O(2)‐dependent effects of nitrite reductase activity in blood and tissue on coupled NO and O(2) transport around arterioles. Adv Exp Med Biol 701: 271‐276, 2011.
 48.Buerk DG, Lahiri S. Evidence that nitric oxide plays a role in O2 sensing from tissue NO and PO2 measurements in cat carotid body. Adv Exp Med Biol 475: 337‐347, 2000.
 49.Buerk DG, Riva CE. Vasomotion and spontaneous low‐frequency oscillations in blood flow and nitric oxide in cat optic nerve head. Microvasc Res 55: 103‐112, 1998.
 50.Buerk DG, Riva CE. Adenosine enhances functional activation of blood flow in cat optic nerve head during photic stimulation independently from nitric oxide. Microvasc Res 64: 254‐264, 2002.
 51.Buerk DG, Riva CE, Cranstoun SD. Nitric oxide has a vasodilatory role in cat optic nerve head during flicker stimuli. Microvasc Res 52: 13‐26, 1996.
 52.Cai H, Li Z, Dikalov S, Holland SM, Hwang J, Jo H, Dudley SC, Jr., Harrison DG. NAD(P)H oxidase‐derived hydrogen peroxide mediates endothelial nitric oxide production in response to angiotensin II. J Biol Chem 277: 48311‐48317, 2002.
 53.Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin‐dependent diabetes. J Clin Invest 90: 2548‐2554, 1992.
 54.Cannon RO, III, Schechter AN, Panza JA, Ognibene FP, Pease‐Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 108: 279‐287, 2001.
 55.Chang HR, Lee RP, Wu CY, Chen HI. Nitric oxide in mesenteric vascular reactivity: A comparison between rats with normotension and hypertension. Clin Exp Pharmacol Physiol 29: 275‐280, 2002.
 56.Chang Y, Kim BK, Yun KE, Cho J, Zhang Y, Rampal S, Zhao D, Jung HS, Choi Y, Ahn J, Lima JA, Shin H, Guallar E, Ryu S. Metabolically‐healthy obesity and coronary artery calcification. J Am Coll Cardiol 63: 2679‐2686, 2014.
 57.Chen K, Pittman RN, Popel AS. Vascular smooth muscle NO exposure from intraerythrocytic SNOHb: A mathematical model. Antioxid Redox Signal 9: 1097‐1110, 2007.
 58.Chen K, Pittman RN, Popel AS. Nitric oxide in the vasculature: Where does it come from and where does it go? A quantitative perspective. Antioxid Redox Signal 10: 1185‐1198, 2008.
 59.Chen K, Popel AS. Nitric oxide production pathways in erythrocytes and plasma. Biorheology 46: 107‐119, 2009.
 60.Chen X, Buerk DG, Barbee KA, Jaron D. A model of NO/O2 transport in capillary‐perfused tissue containing an arteriole and venule pair. Ann Biomed Eng 35: 517‐529, 2007.
 61.Chen X, Jaron D, Barbee KA, Buerk DG. The influence of radial RBC distribution, blood velocity profiles, and glycocalyx on coupled NO/O2 transport. J Appl Physiol 100: 482‐492, 2006.
 62.Chen Y‐A, Messina EJ. Dilation of isolated skeletal muscle arterioles by insulin is endothelium dependent and nitric oxide mediated. Am J Physiol 270: H2120‐H2124, 1996.
 63.Cherney DZ, Reich HN, Scholey JW, Lai V, Slorach C, Zinman B, Bradley TJ. Systemic hemodynamic function in humans with type 1 diabetes treated with protein kinase Cbeta inhibition and renin‐angiotensin system blockade: A pilot study. Can J Physiol Pharmacol 90: 113‐121, 2012.
 64.Chi OZ, Liu X, Weiss HR. Effects of inhibition of neuronal nitric oxide synthase on NMDA‐induced changes in cerebral blood flow and oxygen consumption. Exp Brain Res 148: 256‐260, 2003.
 65.Chu S, Bohlen HG. High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am J Physiol Renal Physiol 287: F384‐F392, 2004.
 66.Closs EI. Expression, regulation and function of carrier proteins for cationic amino acids. Curr Opin Nephrol Hypertens 11: 99‐107, 2002.
 67.Closs EI, Basha FZ, Habermeier A, Forstermann U. Interference of l‐arginine analogues with l‐arginine transport mediated by the y+ carrier hCAT‐2B. Nitric Oxide 1: 65‐73, 1997.
 68.Closs EI, Scheld JS, Sharafi M, Forstermann U. Substrate supply for nitric‐oxide synthase in macrophages and endothelial cells: Role of cationic amino acid transporters. Mol Pharmacol 57: 68‐74, 2000.
 69.Coca SG, Ismail‐Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: Systematic review and meta‐analysis intensive glucose control in type 2 diabetes. Arch Intern Med 172: 761‐769, 2012.
 70.Coleman DA, Khalil RA. Physiologic increases in extracellular sodium salt enhance coronary vasoconstriction and Ca2+ entry. J Cardiovasc Pharmacol 40: 58‐66, 2002.
 71.Cornfield DN. Developmental regulation of oxygen sensing and ion channels in the pulmonary vasculature. Adv Exp Med Biol 661: 201‐220, 2010.
 72.Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim‐Shapiro DB, Schechter AN, Cannon RO, III, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9: 1498‐1505, 2003.
 73.Crawford DW, Cole MA. Performance evaluation of recessed microcathodes: Criteria for tissue PO2 measurement. J Appl Physiol 58: 1400‐1405, 1985.
 74.DeRubertis FR, Craven PA. Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 43: 1‐8, 1994.
 75.Diesen DL, Hess DT, Stamler JS. Hypoxic vasodilation by red blood cells: Evidence for an s‐nitrosothiol‐based signal. Circ Res 103: 545‐553, 2008.
 76.Distasi MR, Unthank JL, Miller SJ. Nox2 and p47(phox) modulate compensatory growth of primary collateral arteries. Am J Physiol Heart Circ Physiol 306: H1435‐H1443, 2014.
 77.Dora KA, Xia J, Duling BR. Endothelial cell signaling during conducted vasomotor responses. Am J Physiol Heart Circ Physiol 285: H119‐H126, 2003.
 78.Dorrance AM, Matin N, Pires PW. The effects of obesity on the cerebral vasculature. Curr Vasc Pharmacol 12: 462‐472, 2014.
 79.Duling BR. Microvascular responses to alterations in oxygen tension. Circ Res 31: 481‐489, 1972.
 80.Duling BR. Oxygen sensitivity of vascular smooth muscle II in vivo studies. Am J Physiol 227: 42‐49, 1974.
 81.Erdos B, Snipes JA, Miller AW, Busija DW. Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and protein kinase C. Diabetes 53: 1352‐1359, 2004.
 82.Fath SW, Burkhart HM, Miller SC, Dalsing MC, Unthank JL. Wall remodeling after wall shear rate normalization in rat mesenteric arterial collaterals. J Vasc Res 35: 257‐264, 1998.
 83.Fatt I. Influence of moving liquid on polarigraphic oxygen sensor current. Fatt, I. The polarigraphic oxygen sensor: Its theory of operation and its application in biology, medicine, and technology. 19‐26, 1976.
 84.Felten SY, Peterson RG, Shea PA, Besch HR, Felten DL. Effects of streptozotocin diabetes on the noradrenergic innervation of the rat heart: A longitudinal histofluorescence and neurochemical study. Brain Res Bull 8: 593‐607, 1982.
 85.Figueroa XF, Duling BR. Gap junctions in the control of vascular function. Antioxid Redox Signal 11: 251‐266, 2009.
 86.Fisslthaler B, Benzing T, Busse R, Fleming I. Insulin enhances the expression of the endothelial nitric oxide synthase in native endothelial cells: A dual role for Akt and AP‐1. Nitric Oxide 8: 253‐261, 2003.
 87.Flam BR, Eichler DC, Solomonson LP. Endothelial nitric oxide production is tightly coupled to the citrulline‐NO cycle. Nitric Oxide 17: 115‐121, 2007.
 88.Foster MW, Pawloski JR, Singel DJ, Stamler JS. Role of circulating S‐nitrosothiols in control of blood pressure. Hypertension 45: 15‐17, 2005.
 89.Fox‐Robichaud A, Payne D, Kubes P. Inhaled NO reaches distal vasculatures to inhibit endothelium‐ but not leukocyte‐dependent cell adhesion. Am J Physiol 277: L1224‐L1231, 1999.
 90.Friedemann MN, Robinson SW, Gerhardt GA. o‐Phenylenediamine‐modified carbon fiber electrodes for the detection of nitric oxide. Anal Chem 68: 2621‐2628, 1996.
 91.Gashev AA, Davis MJ, Zawieja DC. Inhibition of the active lymph pump by flow in rat mesenteric lymphatics and thoracic duct. J Physiol 540: 1023‐1037, 2002.
 92.Gasheva OY, Zawieja DC, Gashev AA. Contraction‐initiated NO‐dependent lymphatic relaxation: A self‐regulatory mechanism in rat thoracic duct. J Physiol 575: 821‐832, 2006.
 93.Gast KB, Smit JW, den HM, Middeldorp S, Rippe RC, le CS, de Koning EJ, Jukema JW, Rabelink TJ, de RA, Rosendaal FR, de MR. Abdominal adiposity largely explains associations between insulin resistance, hyperglycemia and subclinical atherosclerosis: The NEO study. Atherosclerosis 229: 423‐429, 2013.
 94.Gates PE, Boucher ML, Silver AE, Monahan KD, Seals DR. Impaire flow‐mediated dilation with age is not explained by l‐arginine bioavailability or endothelial asymmetric dimethyarginine protein expression. J Appl Physiol 102: 63‐71, 2006.
 95.Gonzalez J, Valls N, Brito R, Rodrigo R. Essential hypertension and oxidative stress: New insights. World J Cardiol 6: 353‐366, 2014.
 96.Granger HJ. Role of the interstitial matrix and lymphatic pump in regulation of transcapillary fluid balance. Microvasc Res 18: 209‐216, 1979.
 97.Granger HJ, Zweifach BW. Mechanics of active lymphatic pumping in rat mesentery. Fed Proc 35: 851, 1976.
 98.Gratton JP, Lin MI, Yu J, Weiss ED, Jiang ZL, Fairchild TA, Iwakiri Y, Groszmann R, Claffey KP, Cheng YC, Sessa WC. Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell 4: 31‐39, 2003.
 99.Green DJ, Dawson EA, Groenewoud HM, Jones H, Thijssen DH. Is flow‐mediated dilation nitric oxide mediated?: A meta‐analysis. Hypertension 63: 376‐382, 2014.
 100.Greenway CV, Scott GD, Zink J. Sites of autoregulatory escape of blood flow in the mesenteric vascular bed. J Physiol 3: 1‐12, 1976.
 101.Gregory SM, Headley SA, Wood RJ. Effects of dietary macronutrient distribution on vascular integrity in obesity and metabolic syndrome. Nutr Rev 69: 509‐519, 2011.
 102.Gunduz F, Kocer G, Ulker S, Meiselman HJ, Baskurt OK, Senturk UK. Exercise training enhances flow‐mediated dilation in spontaneously hypertensive rats. Physiol Res 60: 589‐597, 2011.
 103.Haas TL, Doyle JL, Distasi MR, Norton LE, Sheridan KM, Unthank JL. Involvement of MMPs in the outward remodeling of collateral mesenteric arteries. Am J Physiol Heart Circ Physiol 293: H2429‐H2437, 2007.
 104.Hachiya HL, Halban PA, King GL. Intracellular pathways of insulin transport across vascular endothelial cells. Am J Physiol 255: C459‐C464, 1988.
 105.Hah JM, Martasek P, Roman LJ, Silverman RB. Aromatic reduced amide bond peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. J Med Chem 46: 1661‐1669, 2003.
 106.Hall CN, Garthwaite J. What is the real physiological NO concentration in vivo? Nitric Oxide 21: 92‐103, 2009.
 107.Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, Hamza S, Speed J, Hall ME. Hypertension: Physiology and pathophysiology. Compr Physiol 2: 2393‐2442, 2012.
 108.Hammarstrom AK, Gage PW. Hypoxia and persistent sodium current. Eur Biophys J 31: 323‐330, 2002.
 109.Hardy TA, May JM. Coordinate regulation of l‐arginine uptake and nitric oxide synthase activity in cultured endothelial cells. Free Radic Biol Med 32: 122‐131, 2002.
 110.Hargens AR, Zweifach BW. Contractile stimuli in collecting lymph vessels. Am J Physiol 233: H57‐H65, 1977.
 111.Hein TW, Potts LB, Xu W, Yuen JZ, Kuo L. Temporal development of retinal arteriolar endothelial dysfunction in porcine type 1 diabetes. Invest Ophthalmol Vis Sci 53: 7943‐7949, 2012.
 112.Hein TW, Rosa RH, Jr., Yuan Z, Roberts E, Kuo L. Divergent roles of nitric oxide and rho kinase in vasomotor regulation of human retinal arterioles. Invest Ophthalmol Vis Sci 51: 1583‐1590, 2010.
 113.Heuil DJ, Hallen K, Feelisch M, Grishamn MB. Dynamic state of s‐nitrosothiols in human plasma and whole blood. Free Radical Biology Med 28, 409‐417. 2000.
 114.Huang A, Sun D, Kaley G, Koller A. Estrogen maintains nitric oxide synthesis in arterioles of female hypertensive rats. Hypertension 29: 1351‐1356, 1997.
 115.Huang W, Dai B, Wen Z, Millard RW, Yu XY, Luther K, Xu M, Zhao TC, Yang HT, Qi Z, Lasance K, Ashraf M, Wang Y. Molecular strategy to reduce in vivo collagen barrier promotes entry of NCX1 positive inducible pluripotent stem cells (iPSC(NCX(1)(+))) into ischemic (or injured) myocardium. PLoS One 8: e70023, 2013.
 116.Hudetz AG, Shen H, Kampine JP. Nitric oxide from neuronal NOS plays critical role in cerebral capillary flow response to hypoxia. Am J Physiol 274: H982‐H989, 1998.
 117.Huynh NN, Chin‐Dusting J. Amino acids, arginase and nitric oxide in vascular health. Clin Exp Pharmacol Physiol 33: 1‐8, 2006.
 118.Hyre CE, Unthank JL, Dalsing MC.. Direct in vivo measurement of flow‐dependent nitric oxide production in mesenteric resistance arteries. J Vasc Surg 27: 726‐732, 1998.
 119.Iantorno M, Campia U, Di DN, Nistico S, Forleo GB, Cardillo C, Tesauro M. Obesity, inflammation and endothelial dysfunction. J Biol Regul Homeost Agents 28: 169‐176, 2014.
 120.Ignarro LJ. Nitric oxide: A novel signal transcellular communication. Hypertension 16: 477‐483, 1990.
 121.Inoguchi T, Xia P, Kunisaki M, Higashi S, Feener EP, King G. Insulin's effect on protein kinase C and diacylglycerol induced by diabetes and glucose in vascular tissues. Am J Physiol 267: E369‐E379, 1994.
 122.Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell S‐E, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC B inhibitor. Science 272: 728‐731, 1996.
 123.Ishii H, Koya D, King GL. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 76: 21‐31, 1998.
 124.Jasperse JLLMH. Flow‐induced dilation of rat soleus feed arteries. Am J Physiol 273: H2423‐H2427, 1997.
 125.Jin J‐S, Bohlen HG. Non‐insulin‐dependent diabetes and hyperglycemia impair rat intestinal flow‐mediated regulation. Am J Physiol 272: H728‐H734, 1997.
 126.Jin JS, Bohlen HG. Acute hyperglycemia impairs in vivo myogenic and norepinephrine vasoconstriction. Am J Physiol (in press): 1996.
 127.Kaiser N, Sasson S, Feener EP, Boukobza‐Vardi N, Higashi S, Moller DE, Davidheiser S, Przybylski RJ, King GL. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes 42: 80‐89, 1993.
 128.Kang LS, Reyes RA, Muller‐Delp JM. Aging impairs flow‐induced dilation in coronary arterioles: Role of NO and H(2)O(2). Am J Physiol Heart Circ Physiol 297: H1087‐H1095, 2009.
 129.Keen H, Jarrett RJ, Fuller JH, McCartney P. Hyperglycemia and arterial disease. Diabetes 30: 49‐53, 1981.
 130.Kempson S, Thompson N, Pezzuto L, Glenn BH. Nitric oxide production by mouse renal tubules can be increased by a sodium‐dependent mechanism. Nitric Oxide 17: 33‐43, 2007.
 131.Kielstein JT, Impraim B, Simmel S, Bode‐Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109: 172‐177, 2004.
 132.Kim DD, Kanetaka T, Durán RG, Sanchez FA, Bohlen HG, Durá WN. Independent regulation of periarteriolar and perivenular nitric oxide mechanisms in the in vivo hamster cheek pouch microvasculature. Microcirculation 16: 323‐330, 2009.
 133.King GL, Johnson SM. Receptor‐mediated transport of insulin across endothelial cells. Science 227: 1583‐1585, 1985.
 134.Kirkeby OJ, Kutzsche S, Risoe C, Rise IR. Cerebral nitric oxide concentration and microcirculation during hypercapnia, hypoxia, and high intracranial pressure in pigs. J Clin Neurosci 7: 531‐538, 2000.
 135.Kojima H, Sakurai K, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, Hirata Y, Nagano T. Development of a fluorescent indicator for nitric oxide based on the fluorescein chromophore. Chem Pharm Bull (Tokyo) 46: 373‐375, 1998.
 136.Koller A. Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension. Microcirculation 9: 277‐294, 2002.
 137.Koller A, Huang A. Impaired nitric oxide‐mediated flow‐induced dilation in arterioles of spontaneously hypertensive rats. Circ Res 74: 416‐421, 1994.
 138.Koller A, Huang A. Shear stress‐induced dilation is attenuated in skeletal muscle arterioles of hypertensive rats. Hypertension 25: 758‐763, 1995.
 139.Koller A, Mizuno R, Kaley G. Flow reduces the amplitude and increases the frequency of lymphatic vasomotion: Role of endothelial prostanoids. Am J Physiol 277: R1683‐R1689, 1999.
 140.Kuo L, Davis MJ, Cannon MS, Chilian WM. Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation. Restoration of endothelium‐dependent responses by l‐arginine. Circ Res 70: 465‐476, 1992.
 141.Kuo L, Davis MJ, Chilian WM. Endothelium‐dependent, flow‐induced dilation of isolated coronary arterioles. Am J Physiol 259: H1063‐H1070, 1990.
 142.Laakso M, Edelman SV, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: A novel mechanism for insulin resistance. J Clin Invest 85: 1844‐1852, 1990.
 143.Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin‐mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 41: 1076‐1083, 1992.
 144.Lahiri S, Buerk DG. Vascular and metabolic effects of nitric oxide synthase inhibition evaluated by tissue PO2 measurements in carotid body. Adv Exp Med Biol 454: 455‐460, 1998.
 145.Lamkin‐Kennard KA, Buerk DG, Jaron D. Interactions between NO and O2 in the microcirculation: A mathematical analysis. Microvasc Res 68: 38‐50, 2004.
 146.Lancaster JR, Jr. A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide 1: 18‐30, 1997.
 147.Lash JM, Nase GP, Bohlen HG. Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle. Am J Physiol 277, H1513‐H1520. 1999.
 148.Lauer T, Preik M, Rassaf T, Strauer BE, Deussen A, Feelisch M, Kelm M. Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proc Natl Acad Sci U S A 98: 12814‐12819, 2001.
 149.Laurindo FRM, Pedro MA, Barbeiro HV, Pileggi F, Carvalho MHCC, Augusto O, da Luz PL. Vascular free radical release: Ex vivo and in vivo evidence for a flow‐dependent endothelial mechanism. Circ Res 74: 700‐709, 1994.
 150.Leblanc AJ, Reyes R, Kang LS, Dailey RA, Stallone JN, Moningka NC, Muller‐Delp JM. Estrogen replacement restores flow‐induced vasodilation in coronary arterioles of aged and ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 297: R1713‐R1723, 2009.
 151.Lee IK, Kim HS, Bae JH. Endothelial dysfunction: Its relationship with acute hyperglycaemia and hyperlipidemia. Int J Clin Pract Suppl 129: 59‐64, 2002.
 152.Lee TJ, Yu JG. L‐Citrulline recycle for synthesis of NO in cerebral perivascular nerves and endothelial cells. Ann N Y Acad Sci 962: 73‐80, 2002.
 153.Li C, Huang W, Harris MB, Goolsby JM, Venema RC. Interaction of the endothelial nitric oxide synthase with the CAT‐1 arginine transporter enhances NO release by a mechanism not involving arginine transport. Biochem J 386: 567‐574, 2005.
 154.Liao JC, Hein TW, Vaughn MW, Huang KT, Kuo L. Intravascular flow decreases erythrocyte consumption of nitric oxide. Proc Natl Acad Sci U S A 96: 8757‐8761, 1999.
 155.Lima B, Forrester MT, Hess DT, Stamler JS. S‐nitrosylation in cardiovascular signaling. Circ Res 106: 633‐646, 2010.
 156.Lindauer U, Kunz A, Schuh‐Hofer S, Vogt J, Dreier JP, Dirnagl U. Nitric oxide from perivascular nerves modulates cerebral arterial pH reactivity. Am J Physiol Heart Circ Physiol 281: H1353‐H1363, 2001.
 157.Liu X, Miller MJ, Joshi MS, Sadowska‐Krowicka H, Clark DA, Lancaster JR, Jr. Diffusion‐limited reaction of free nitric oxide with erythrocytes. J Biol Chem 273: 18709‐18713, 1998.
 158.Loesch A, Burnstock G. Perivascular nerve fibres and endothelial cells of the rat basilar artery: Immuno‐gold labelling of antigenic sites for type I and type III nitric oxide synthase. J Neurocytol 27: 197‐204, 1998.
 159.Lu X, Guo X, Wassall CD, Kemple MD, Unthank JL, Kassab GS. Reactive oxygen species cause endothelial dysfunction in chronic flow overload. J Appl Physiol (1985) 110: 520‐527, 2011.
 160.Lyamina NP, Dolotovskaya PV, Lyamina SV, Malyshev IY, Manukhina EB. Nitric oxide production and intensity of free radical processes in young men with high normal and hypertensive blood pressure. Med Sci Monit 9: CR304‐CR310, 2003.
 161.Lyamina NP, Lyamina SV, Senchiknin VN, Mallet RT, Downey HF, Manukhina EB. Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in patients with arterial hypertension. J Hypertens 29: 2265‐2272, 2011.
 162.Lynch FM, Austin C, Heagerty AM, Izzard AS. Adenosine and hypoxic dilation of rat coronary small arteries: Roles of the ATP‐sensitive potassium channel, endothelium, and nitric oxide. Am J Physiol Heart Circ Physiol 290: H1145‐H1150, 2006.
 163.MacAllister RJ, Calver AL, Riezebos J, Collier J, Vallance P. Relative potency and arteriovenous selectivity of nitrovasodilators on human blood vessels: An insight into the targeting of nitric oxide delivery. J Pharmacol Exp Ther 273: 154‐160, 1995.
 164.Malinski T, Bailey F, Zhang ZG, Chopp M. Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 13: 355‐358, 1993.
 165.Malinski T, Mesaros S, Tomboulian P. Nitric oxide measurement using electrochemical methods. Meth Enzym 268: 58‐69, 1996.
 166.Malinski T, Taha Z. Nitric oxide release from a single cell measured in situ by a porphyrinic‐based microsensor. Nature 358: 676‐678, 1992.
 167.Manrique C, Lastra G, Sowers JR. New insights into insulin action and resistance in the vasculature. Ann N Y Acad Sci 1311: 138‐150, 2014.
 168.Markos F, Ruane OT, Noble MI. What is the mechanism of flow‐mediated arterial dilatation. Clin Exp Pharmacol Physiol 40: 489‐494, 2013.
 169.Maruf FA, Salako BL, Akinpelu AO. Can aerobic exercise complement antihypertensive drugs to achieve blood pressure control in individuals with essential hypertension?. J Cardiovasc Med (Hagerstown) 15: 456‐462, 2014.
 170.Matrougui K, Maclouf J, Levy BI, Henrion D. Impaired nitric oxide‐ and prostaglandin‐mediated responses to flow in resistance arteries of hypertensive rats. Hypertension 30: 942‐947, 1997.
 171.Mayhan WG. Superoxide dismutase partially restores impaired dilatation of the basilar artery during diabetes mellitus. Brain Res 760: 204‐209, 1997.
 172.Mayhan WG, Arrick DM, Sharpe GM, Patel KP, Sun H. Inhibition of NAD(P)H oxidase alleviates impaired NOS‐dependent responses of pial arterioles in type 1 diabetes mellitus. Microcirculation 13: 567‐575, 2006.
 173.Mayhan WG, Patel KP. Acute effects of glucose on reactivity of cerebral microcirculation: Role of activation of protein kinase C. Am J Physiol 269: H1297‐H1302, 1995.
 174.Mayhan WG, Sun H, Mayhan JF, Patel KP. Influence of exercise on dilatation of the basilar artery during diabetes mellitus. J Appl Physiol 96: 1730‐1737, 2004.
 175.McHale NG, Roddie IC. The effect of transmural pressure on pumping activity in isolated bovine lymphatic vessels. J Physiol (Lond) 261: 255‐269, 1976.
 176.Mikulic I, Petrik J, Galesic K, Romic Z, Cepelak I, Zeljko‐Tomic M. Endothelin‐1, big endothelin‐1, and nitric oxide in patients with chronic renal disease and hypertension. J Clin Lab Anal 23: 347‐356, 2009.
 177.Miura H, Liu Y, Gutterman DD. Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: Contribution of nitric oxide and Ca2+‐activated K+ channels. Circulation 99: 3132‐3138, 1999.
 178.Mizuno R, Dornyei G, Koller A, Kaley G. Myogenic responses of isolated lymphatics: Modulation by endothelium. Microcirculation 4: 413‐420, 1997.
 179.Mizuno R, Koller A, Kaley G. Regulation of the vasomotor activity of lymph microvessels by nitric oxide and prostaglandins. Am J Physiol 274: R790‐R796, 1998.
 180.Moriel P, Sevanian A, Ajzen S, Zanella MT, Plavnik FL, Rubbo H, Abdalla DS. Nitric oxide, cholesterol oxides and endothelium‐dependent vasodilation in plasma of patients with essential hypertension. Braz J Med Biol Res 35: 1301‐1309, 2002.
 181.Muiesan ML, Salvetti M, Monteduro C, Rizzoni D, Zulli R, Corbellini C, Brun C, Agabiti‐Rosei E. Effect of treatment on flow‐dependent vasodilation of the brachial artery in essential hypertension. Hypertension 33: 575‐580, 1999.
 182.Mungrue IN, Bredt DS. nNOS at a glance: Implications for brain and brawn. J Cell Sci 117: 2627‐2629, 2004.
 183.Murad F. Signal Transduction using nitric oxide and cyclic guanosine monophosphate. JAMA 276, 1189‐1192. 1996.
 184.Naruse K, Rask‐Madsen C, Takahara N, Ha SW, Suzuma K, Way KJ, Jacobs JR, Clermont AC, Ueki K, Ohshiro Y, Zhang J, Goldfine AB, King GL. Activation of vascular protein kinase C‐beta inhibits Akt‐dependent endothelial nitric oxide synthase function in obesity‐associated insulin resistance. Diabetes 55: 691‐698, 2006.
 185.Nase GP, Tuttle J, Bohlen HG. Reduced perivascular PO2 increases nitric oxide release from endothelial cells. Am J Physiol Heart Circ Physiol 285: H507‐H515, 2003.
 186.Nathan DM. Understanding the long‐term benefits and dangers of intensive therapy of diabetes. Arch Intern Med 172: 769‐770, 2012.
 187.Ng ES, Jourd'heuil D, McCord JM, Hernandez D, Yasui M, Knight D, Kubes P. Enhanced S‐nitroso‐albumin formation from inhaled NO during ischemia/reperfusion. Circ Res 94: 559‐565, 2004.
 188.Ngai AC, Winn HR. Modulation of cerebral arteriolar diameter by intraluminal flow and pressure. Circ Res 77: 832‐840, 1995.
 189.Ngo AT, Jensen LJ, Riemann M, Holstein‐Rathlou NH, Torp‐Pedersen C. Oxygen sensing and conducted vasomotor responses in mouse cremaster arterioles in situ. Pflugers Arch 460: 41‐53, 2010.
 190.Ngo AT, Riemann M, Holstein‐Rathlou NH, Torp‐Pedersen C, Jensen LJ. Significance of K(ATP) channels, L‐type Ca(2)(+) channels and CYP450‐4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo. BMC Physiol 13: 8, 2013.
 191.O'Connor DT, Tyrell EA, Kailasam MT, Miller LM, Martinez JA, Henry RR, Parmer RJ, Gabbai FB. Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: Mechanisms and consequences. Hypertension 37: 898‐906, 2001.
 192.Ohhashi T, Azuma T, Sakaguchi M. Active and passive mechanical characteristics of bovine mesenteric lymphatics. Am J Physiol 239: H88‐H95, 1980.
 193.Ong KL, McClelland RL, Rye KA, Cheung BM, Post WS, Vaidya D, Criqui MH, Cushman M, Barter PJ, Allison MA. The relationship between insulin resistance and vascular calcification in coronary arteries, and the thoracic and abdominal aorta: The Multi‐Ethnic Study of Atherosclerosis. Atherosclerosis 236: 257‐262, 2014.
 194.Orlov RS, Lobacheva A. Intravascular pressure and spontaneous contraction of the lymphatics. Bull Exp Biol Med 83: 448‐450, 1977.
 195.Palm F, Nordquist L, Buerk DG. Nitric oxide in the kidney; direct measurements of bioavailable renal nitric oxide. Adv Exp Med Biol 599: 117‐123, 2007.
 196.Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium‐derived relaxing factor. Nature 327: 524‐526, 1987.
 197.Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Eur Heart J 34: 2436‐2443, 2013.
 198.Park JB, Charbonneau F, Schiffrin EL. Correlation of endothelial function in large and small arteries in human essential hypertension. J Hypertens 19: 415‐420, 2001.
 199.Pezzuto L, Bohlen HG. Extracellular arginine rapidly dilates in vivo intestinal arteries and arterioles through a nitric oxide mechanism. Microcirculation 15: 123‐135, 2008.
 200.Phillips SA, Hatoum OA, Gutterman DD. The mechanism of flow‐induced dilation in human adipose arterioles involves hydrogen peroxide during CAD. Am J Physiol Heart Circ Physiol 292: H93‐100, 2007.
 201.Pittman RN, Duling BR. Oxygen sensitivity of vascular smooth muscle: I in vitro studies. Microvasc Res 6: 202‐211, 1973.
 202.Plantinga Y, Ghiadoni L, Magagna A, Giannarelli C, Franzoni F, Taddei S, Salvetti A. Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients. Am J Hypertension 20: 392‐397, 2007.
 203.Plantinga Y, Ghiadoni L, Magagna A, Giannarelli C, Penno G, Pucci L, Taddei S, Del PS, Salvetti A. Peripheral wave reflection and endothelial function in untreated essential hypertensive patients with and without the metabolic syndrome. J Hypertens 26: 1216‐1222, 2008.
 204.Pohl P, Saparov SM, Antonenko YN. The size of the unstirred layer as a function of the solute diffusion coefficient. Biophys J 75: 1403‐1409, 1998.
 205.Rajapakse NW, Mattson DL. Role of cellular l‐arginine uptake and nitric oxide production on renal blood flow and arterial pressure regulation. Curr Opin Nephrol Hypertens 22: 45‐50, 2013.
 206.Rassaf T, Kleinbongard P, Preik M, Dejam A, Gharini P, Lauer T, Erckenbrecht J, Duschin A, Schulz R, Heusch G, Feelisch M, Kelm M. Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: Experimental and clinical Study on the fate of NO in human blood. Circ Res 91: 470‐477, 2002.
 207.Rassaf T, Preik M, Kleinbongard P, Lauer T, Heiss C, Strauer BE, Feelisch M, Kelm M. Evidence for in vivo transport of bioactive nitric oxide in human plasma. J Clin Invest 109: 1241‐1248, 2002.
 208.Reneman RS, Arts T, Hoeks AP. Wall shear stress–an important determinant of endothelial cell function and structure–in the arterial system in vivo. Discrepancies with theory. J Vasc Res 43: 251‐269, 2006.
 209.Reynolds JD, Bennett KM, Cina AJ, Diesen DL, Henderson MB, Matto F, Plante A, Williamson RA, Zandinejad K, Demchenko IT, Hess DT, Piantadosi CA, Stamler JS. S‐nitrosylation therapy to improve oxygen delivery of banked blood. Proc Natl Acad Sci U S A 110: 11529‐11534, 2013.
 210.Robertson SC, Loftus CM. Effect of N‐methyl‐D‐aspartate and inhibition of neuronal nitric oxide on collateral cerebral blood flow after middle cerebral artery occlusion. Neurosurgery 42: 117‐123, 1998.
 211.Rodrigo J, Riveros‐Moreno V, Bentura ML, Uttenthal LO, Higgs EA, Fernandez AP, Polak JM, Moncada S, Martinez‐Murillo R. Subcellular localization of nitric oxide synthase in the cerebral ventricular system, subfornical organ, area postrema, and blood vessels of the rat brain. J Comp Neurol 378: 522‐534, 1997.
 212.Rosenbaugh EG, Savalia KK, Manickam DS, Zimmerman MC. Antioxidant‐based therapies for angiotensin II‐associated cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 304: R917‐R928, 2013.
 213.Rubin MJ, Bohlen HG. Cerebral vascular autoregulation of blood flow and tissue PO2 in diabetic rats. Am J Physiol 249: H540‐H546, 1985.
 214.Saito Y, Eraslan A, Hester RL. Role of endothelium‐derived relaxing factors in arteriolar dilation during muscle contraction elicited by electrical field stimulation. Microcirculation 1: 195‐201, 1994.
 215.Schirmer SH, van RN. Stimulation of collateral artery growth: A potential treatment for peripheral artery disease. Expert Rev Cardiovasc Ther 2: 581‐588, 2004.
 216.Schneiderman G, Goldstick TK. Oxygen electrode design criteria and performance characteristics: Recessed cathode. J Appl Physiol 45: 145‐154, 1978.
 217.Schwaninger RM, Sun H, Mayhan WG. Impaired nitric oxide synthase‐dependent dilatation of cerebral arterioles in type II diabetic rats. Life Sci 73: 3415‐3425, 2003.
 218.Segal SS, Duling BR. Communication between feed arteries and microvessels in hamster striated muscle: Segmental vascular responses are functionally coordinated. Circ Res 59: 283‐290, 1986.
 219.Segal SS, Duling BR. Propagation of vasodilation in resistance vessels of the hamster: Development and review of a working hypothesis. Circ Res 61: II‐20‐II‐25, 1987.
 220.Semlitsch T, Jeitler K, Hemkens LG, Horvath K, Nagele E, Schuermann C, Pignitter N, Herrmann KH, Waffenschmidt S, Siebenhofer A. Increasing physical activity for the treatment of hypertension: A systematic review and meta‐analysis. Sports Med 43: 1009‐1023, 2013.
 221.Shantsila A, Dwivedi G, Shantsila E, Butt M, Beevers DG, Lip GY. Persistent macrovascular and microvascular dysfunction in patients with malignant hypertension. Hypertension 57: 490‐496, 2011.
 222.Sheetz MJ, Aiello LP, Davis MD, Danis R, Bek T, Cunha‐Vaz J, Shahri N, Berg PH. The effect of the oral PKC beta inhibitor ruboxistaurin on vision loss in two phase 3 studies. Invest Ophthalmol Vis Sci 54: 1750‐1757, 2013.
 223.Sheng H, Reynolds JD, Auten RL, Demchenko IT, Piantadosi CA, Stamler JS, Warner DS. Pharmacologically augmented S‐nitrosylated hemoglobin improves recovery from murine subarachnoid hemorrhage. Stroke 42: 471‐476, 2011.
 224.Shirasawa Y, Ikomi F, Ohhashi T. Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat mesentery in vivo. Am J Physiol Gastrointest Liver Physiol 278: G551‐G556, 2000.
 225.Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells. Annu Rev Physiol 67: 99‐145, 2005.
 226.Solomonson LP, Flam BR, Pendleton LC, Goodwin BL, Eichler DC. The caveolar nitric oxide synthase/arginine regeneration system for NO production in endothelial cells. J Exp Biol 206: 2083‐2087, 2003.
 227.Sparacino‐Watkins CE, Lai YC, Gladwin MT. Nitrate‐nitrite‐nitric oxide pathway in pulmonary arterial hypertension therapeutics. Circulation 125: 2824‐2826, 2012.
 228.Stamler JS. S‐nitrosothiols in the blood: Roles, amounts, and methods of analysis. Circ Res 94: 414‐417, 2004.
 229.Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin‐mediated skeletal muscle vasodilation is nitric oxide dependent: A novel action of insulin to increase nitric oxide release. J Clin Invest 94: 1172‐1179, 1994.
 230.Sun D, Huang A, Koller A, Kaley G. Endothelial K(ca) channels mediate flow‐dependent dilation of arterioles of skeletal muscle and mesentery. Microvasc Res 61: 179‐186, 2001.
 231.Taguchi K, Kobayashi T, Takenouchi Y, Matsumoto T, Kamata K. Angiotensin II causes endothelial dysfunction via the GRK2/Akt/eNOS pathway in aortas from a murine type 2 diabetic model. Pharmacol Res 64: 535‐546, 2011.
 232.Taha Z, Kiechle F, Malinski T. Oxidation of nitric oxide by oxygen in biological systems monitored by porphyrinic sensor. Biochem Biophys Res Commun 188: 734‐739, 1992.
 233.Taka T, Ohta Y, Seki J, Giddings JC, Yamamoto J. Impaired flow‐mediated vasodilation in vivo and reduced shear‐induced platelet reactivity in vitro in response to nitric oxide in prothrombotic, stroke‐prone spontaneously hypertensive rats. Pathophysiol Haemost Thromb 32: 184‐189, 2002.
 234.Thom SR, Bhopale V, Fisher D, Manevich Y, Huang PL, Buerk DG. Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: An oxidative stress response. J Neurobiol 51: 85‐100, 2002.
 235.Thom SR, Fisher D, Zhang J, Bhopale VM, Ohnishi ST, Kotake Y, Ohnishi T, Buerk DG. Stimulation of perivascular nitric oxide synthesis by oxygen. Am J Physiol Heart Circ Physiol 284: H1230‐H1239, 2003.
 236.Thomas DD, Liu X, Kantrow SP, Lancaster JR, Jr. The biological lifetime of nitric oxide: Implications for the perivascular dynamics of NO and O2. Proc Natl Acad Sci U S A 98: 355‐360, 2001.
 237.Thomas DD, Ridnour LA, Isenberg JS, Flores‐Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA. The chemical biology of nitric oxide: Implications in cellular signaling. Free Radic Biol Med 45: 18‐31, 2008.
 238.Tilly BC, Tertoolen LGJ, de Jonge HR. Protein tyrosine phosphorylation is involved in osmoregulation of ionic conductances. J Biologic Chem 268: 19919‐19922, 1993.
 239.Toda N, Okamura T. Obesity impairs vasodilatation and blood flow increase mediated by endothelial nitric oxide: An overview. J Clin Pharmacol 53: 1228‐1239, 2013.
 240.Tsai AG, Acero C, Nance PR, Cabrales P, Frangos JA, Buerk DG, Intaglietta M. Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion. Am J Physiol Heart Circ Physiol 288: H1730‐H1739, 2005.
 241.Tsai AG, Cabrales P, Manjula BN, Acharya SA, Winslow RM, Intaglietta M. Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell‐free hemoglobin oxygen carriers. Blood 108: 3603‐3610, 2006.
 242.Tschudi MR, Mesaros S, Luscher TF, Malinski T. Direct in situ measurement of nitric oxide in mesenteric resistance arteries: Increased decomposition by superoxide in hypertension. Hypertension 27: 32‐35, 1996.
 243.Tsunemoto H, Ikomi F, Ohhashi T. Flow‐mediated release of nitric oxide from lymphatic endothelial cells of pressurized canine thoracic duct. Jpn J Physiol 53: 157‐163, 2003.
 244.Tulis DA, Unthank JL, Prewitt RL. Flow‐induced arterial remodeling in rat mesenteric vasculature. Am J Physiol 274: H874‐H882, 1998.
 245.Tune JD. Control of coronary blood flow during hypoxemia. Adv Exp Med Biol 618: 25‐39, 2007.
 246.Tuttle JL, Nachreiner RD, Bhuller AS, Condict KW, Connors BA, Herring BP, Dalsing MC, Unthank JL. Shear level influences resistance artery remodeling: Wall dimensions, cell density, and eNOS expression. Am J Physiol Heart Circ Physiol 281: H1380‐H1389, 2001.
 247.Unthank JL, McClintick JN, Labarrere CA, Li L, Distasi MR, Miller SJ. Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat: Insight from microarray analysis. Physiol Rep 1: e0005, 2013.
 248.Unthank JL, Nixon JC, Burkhart HM, Fath SW, Dalsing MC. Early collateral and microvascular adaptations to intestinal artery occlusion in rat. Am J Physiol 271: H914‐H923, 1996.
 249.Vallance P, Patton S, Bhagat K, MacAllister R, Radomski M, Moncada S, Malinski T. Direct measurement of nitric oxide in human beings. Lancet 345: 153‐154, 1995.
 250.Vaughn MW, Kuo L, Liao JC. Effective diffusion distance of nitric oxide in microcirculation. Am J Physiol 274: H1705‐H1714, 1998.
 251.Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr Diab Rep 3: 279‐288, 2003.
 252.Viswambharan H, Sukumar P, Sengupta A, Cubbon R, Imrie H, Gage M, Haywood N, Skromna A, Kate G, V, Galloway S, Turner J, Yuldasheva N, Shah A, Santos C, Beech D, Wheatcroft S, Kearney M. 173 Increasing insulin sensitivity in the endothelium leads to reduced nitric oxide bioavailability. Heart 100(Suppl 3): A98, 2014.
 253.von der Weid PY, Crowe MJ, van Helden DF. Endothelium‐dependent modulation of pacemaking in lymphatic vessels of the guinea‐pig mesentery. J Physiol 493(Pt 2): 563‐575, 1996.
 254.von der Weid PY, Zhao J, van Helden DF. Nitric oxide decreases pacemaker activity in lymphatic vessels of guinea pig mesentery. Am J Physiol Heart Circ Physiol 280: H2707‐H2716, 2001.
 255.Vukosavljevic N, Jaron D, Barbee KA, Buerk DG. Quantifying the l‐arginine paradox in vivo. Microvasc Res 71: 48‐54, 2006.
 256.Wang H, Wang AX, Aylor K, Barrett EJ. Nitric oxide directly promotes vascular endothelial insulin transport. Diabetes 62: 4030‐4042, 2013.
 257.Way KJ, Isshiki K, Suzuma K, Yokota T, Zvagelsky D, Schoen FJ, Sandusky GE, Pechous PA, Vlahos CJ, Wakasaki H, King GL. Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes. Diabetes 51: 2709‐2718, 2002.
 258.Weston KS, Wisloff U, Coombes JS. High‐intensity interval training in patients with lifestyle‐induced cardiometabolic disease: A systematic review and meta‐analysis. Br J Sports Med 48: 1227‐1234, 2014.
 259.Whalen WJ, Nair P, Ganfield RA. Measurements of oxygen tension in tissues with a micro oxygen electrode. Microvasc Res 5: 254‐262, 1973.
 260.Whalen WJ, Riley J, Nair P. A microelectrode for measuring intracellular PO2. J Appl Physiol 23(5): 798‐801, 1967.
 261.Wickman C, Kramer H. Obesity and kidney disease: Potential mechanisms 1. Semin Nephrol 33: 14‐22, 2013.
 262.Williams MA, Chakravarthy U. Evidence underlying the clinical management of diabetic macular oedema. Clin Med 13: 353‐357, 2013.
 263.Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL. Characterization of the mechanism for the chronic activation of diacylglycerol‐protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 43: 1122‐1129, 1994.
 264.Xu L, Chen J, Li XY, Ren S, Huang CX, Wu G, Li XY, Jiang XJ. Analysis of Na(+)/Ca (2+) exchanger (NCX) function and current in murine cardiac myocytes during heart failure. Mol Biol Rep 39: 3847‐3852, 2012.
 265.Yamaji R, Fujita K, Takahashi S, Yoneda H, Nagao K, Masuda W, Naito M, Tsuruo T, Miyatake K, Inui H, Nakano Y. Hypoxia up‐regulates glyceraldehyde‐3‐phosphate dehydrogenase in mouse brain capillary endothelial cells: Involvement of Na+/Ca2+ exchanger. Biochim Biophys Acta 1593: 269‐276, 2003.
 266.Yokota T, Ma RC, Park JY, Isshiki K, Sotiropoulos KB, Rauniyar RK, Bornfeldt KE, King GL. Role of protein kinase C on the expression of platelet‐derived growth factor and endothelin‐1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes 52: 838‐845, 2003.
 267.Yoshida T, Limmroth V, Irikura K, Moskowitz MA. The NOS inhibitor, 7‐nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels. J Cereb Blood Flow Metab 14: 924‐929, 1994.
 268.Younk LM, Lamos EM, Davis SN. The cardiovascular effects of insulin. Expert Opin Drug Saf 13: 955‐966, 2014.
 269.Yousef T, Neubacher U, Eysel UT, Volgushev M. Nitric oxide synthase in rat visual cortex: An immunohistochemical study. Brain Res Brain Res Protoc 13: 57‐67, 2004.
 270.Yurcisin BM, Davison TE, Bibbs SM, Collins BH, Stamler JS, Reynolds JD. Repletion of S‐nitrosohemoglobin improves organ function and physiological status in swine after brain death. Ann Surg 257: 971‐977, 2013.
 271.Zacharia IG, Deen WM. Diffusivity and solubility of nitric oxide in water and saline. Ann Biomed Eng 33: 214‐222, 2005.
 272.Zani BG, Bohlen HG. Sodium channels are required during in vivo sodium chloride hyperosmolarity to stimulate an increase in intestinal endothelial nitric oxide production. Am J Physiol Heart Circ Physiol 288: H89‐H95, 2004.
 273.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.
 274.Zani BG, Bohlen HG. Transport of extracellular l‐arginine via the cationic amino acid transporter is required during in vivo endothelial nitric oxide production. Am J Physiol Heart Circ Physiol 289: H1381‐H1390, 2005.
 275.Zgheel F, Alhosin M, Rashid S, Burban M, Auger C, Schini‐Kerth VB. Redox‐sensitive induction of Src/PI3‐kinase/Akt and MAPKs pathways activate eNOS in response to EPA:DHA 6:1. PLoS One 9: e105102, 2014.
 276.Zhang ZG, Chopp M, Bailey F, Malinski T. Nitric oxide changes in the rat brain after transient middle cerebral artery occlusion. J Neurol Sci 128: 22‐27, 1995.
 277.Zhou X, Bohlen HG, Miller SJ, Unthank JL. NAD(P)H oxidase‐derived peroxide mediates elevated basal and impaired flow‐induced NO production in SHR mesenteric arteries in vivo. Am J Physiol Heart Circ Physiol 295: H1008‐H1016, 2008.
 278.Zhou X, Bohlen HG, Unthank JL, Miller SJ. Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase‐derived peroxide. Am J Physiol Heart Circ Physiol 297: H2227‐H2233, 2009.
 279.Ziegler MA, Distasi MR, Bills RG, Miller SJ, Alloosh M, Murphy MP, Akingba AG, Sturek M, Dalsing MC, Unthank JL. Marvels, mysteries, and misconceptions of vascular compensation to peripheral artery occlusion. Microcirculation 17: 3‐20, 2010.
 280.Zuo L, Rose BA, Roberts WJ, He F, Banes‐Berceli AK. Molecular characterization of reactive oxygen species in systemic and pulmonary hypertension. Am J Hypertension 27: 643‐650, 2014.

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Harold Glenn Bohlen. Nitric Oxide and the Cardiovascular System. Compr Physiol 2015, 5: 803-828. doi: 10.1002/cphy.c140052