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Nitric Oxide and the Cardiovascular System

Harold Glenn Bohlen

10.1002/cphy.c140052

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



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 (33).
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 (28).
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 (28).
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 (33).
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 (37).
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 (37).
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 (37).
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 (276).
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 (276).
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 (15). 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 (15).
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 (27).
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 (35).


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 (33).


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 (28).


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 (28).


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 (33).


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 (37).


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 (37).


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 (37).


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 (276).


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 (276).


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 (15). 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 (15).


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 (27).


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 (35).
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Article Title: Nitric Oxide and the Cardiovascular System
 

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