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Salt, Angiotensin II, Superoxide, and Endothelial Function

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ABSTRACT

Proper function of the vascular endothelium is essential for cardiovascular health, in large part due to its antiproliferative, antihypertrophic, and anti‐inflammatory properties. Crucial to the protective role of the endothelium is the production and liberation of nitric oxide (NO), which not only acts as a potent vasodilator, but also reduces levels of reactive oxygen species, including superoxide anion (O2•−). Superoxide anion is highly injurious to the vasculature because it not only scavenges NO molecules, but has other damaging effects, including direct oxidative disruption of normal signaling mechanisms in the endothelium and vascular smooth muscle cells. The renin‐angiotensin system plays a crucial role in the maintenance of normal blood pressure. This function is mediated via the peptide hormone angiotensin II (ANG II), which maintains normal blood volume by regulating Na+ excretion. However, elevation of ANG II above normal levels increases O2•− production, promotes oxidative stress and endothelial dysfunction, and plays a major role in multiple disease conditions. Elevated dietary salt intake also leads to oxidant stress and endothelial dysfunction, but these occur in the face of salt‐induced ANG II suppression and reduced levels of circulating ANG II. While the effects of abnormally high levels of ANG II have been extensively studied, far less is known regarding the mechanisms of oxidant stress and endothelial dysfunction occurring in response to chronic exposure to abnormally low levels of ANG II. The current article focuses on the mechanisms and consequences of this less well understood relationship among salt, superoxide, and endothelial function. © 2016 American Physiological Society. Compr Physiol 6:215‐254, 2016.

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Figure 1. Figure 1. Kaplan‐Meier survival curves for normotensive salt‐resistant subjects (N + R), normotensive SS subjects (N + S), hypertensive salt‐resistant subjects (H + R), and hypertensive SS subjects (H + S) over the follow‐up period from initial testing. From Weinberger et al., Ref. .
Figure 2. Figure 2. Flow‐induced dilation of coronary arterioles of normal salt (NS, n‐5, A) and low‐salt (LS, n = 7, B) diet dogs in the control condition and after incubating vessels with apocynin (APO—10−5 M), or apocynin plus Nω‐nitro‐l‐arginine methyl ester (l‐NAME, 3 × 10−4 M) for 30 min. Changes in diameter were normalized to passive diameter (PD) of the vessels. *Significant difference from the curve of APO. From Huang et al., Ref. .
Figure 3. Figure 3. Protein expression of gp91phox and p47phox in coronary arterioles of dogs. Densitometry data were summarized from two blots. *Significant difference from NS dogs. Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH)‐glyceraldehyde‐3‐phosphate dehydrogenase. From Huang et al., Ref. .
Figure 4. Figure 4. Diameter changes to increasing concentrations of ACh in norepinephrine‐precontracted mesenteric arteries from Sprague‐Dawley rats fed either a low‐salt (LS) diet (left; n = 8) or a high‐salt diet (right; n = 8‐9).*P < 0.05 versus precontracted control diameters in the absence of 10−4 M Nω‐Nitro‐l‐arginine methyl ester (l‐NAME). From Raffai et al., Ref. .
Figure 5. Figure 5. DHE staining to indicate superoxide production in mesenteric arteries from rats fed low‐salt diet (A); high‐salt diet (B) and high‐salt diet with tempol in the vessel chamber (C). (D) Summarized data showing changes in the slope of DHE fluorescence intensity during resting conditions in mesenteric arteries from rats fed low‐ and high‐salt diet, with and without tempol in the tissue bath. Data are shown as means ± SEM (n = number of rats).*P < 0.05 versus fluorescence intensity from low salt control; P < 0.05 versus control group on the same diet. From Zhu et al., Ref. .
Figure 6. Figure 6. Arteriolar responses to iontophoretically applied ACh under normal superfusate (A) and a superfusate containing 50 U/mL SOD +50 U/mL catalase in the spinotrapezius muscle of rats fed low‐ (LS) or high‐salt (HS) diet (B) *P < 0.05 versus low salt. P < 0.05 versus high salt at 5 nA; P < 0.05 versus HS at 20 nA. From Lenda et al., Ref. .
Figure 7. Figure 7. Effect of apocynin (100 μmol/L) and oxipurinol (100 μmol/L) on the basal level of NO production, evaluated as the slope ratio of DAF‐2T fluorescence intensity in mesenteric resistance arteries from rats fed high‐ or low‐salt diet. Data are shown as means ± SEM, and n = number of rats. *P < 0.05 versus corresponding vessels from rats fed low‐salt diet; P < 0.05 versus untreated control. Replotted from Zhu et al., Ref. .
Figure 8. Figure 8. (Top) Arteriolar wall BH4 content in mice fed normal salt or high‐salt diet, with or without l‐arginine (l‐ARG) supplementation. *P < 0.05 versus untreated and L‐ARG supplemented normal salt. (Bottom) Magnitude of responses to ACh, under normal superfusate (control) and in the presence of Nω‐nitro‐l‐arginine methyl ester (l‐NAME), in mice fed normal‐ or high‐salt diet, with or without l‐arginine supplementation. P < 0.05 versus control. Replotted from Nurkiewicz et al., Ref. .
Figure 9. Figure 9. Afferent arteriolar diameter in response to changing renal perfusion pressure in kidney using the in vitro juxtamedullary nephron technique. Responses of normal salt (NS), high salt (HS), normal salt plus apocynin (Apo), and high salt plus Apo groups are expressed as a percentage of the control diameter. The autoregulatory profile ranged from 65 to 170 mmHg. *P < 0.05, high‐salt versus normal‐salt groups; P < 0.05, high salt versus high salt plus APO groups. From Fellner et al., Ref. .
Figure 10. Figure 10. Brachial artery flow‐mediated dilation (FMD) for men (white bars) and women (black bars) after low‐salt (LS) and high‐salt (HS) diet. *P < 0.05 compared to respective low salt; P < 0.05 compared to men on high salt. From Lennon‐Edwards et al., Ref. .
Figure 11. Figure 11. Brachial artery flow‐mediated dilation (FMD) at fasting (time 0) and in response to consumption of a low‐salt meal and a high‐salt meal. n = 16 (10 women and 6 men). *Significantly different from the high‐salt meal, P < 0.01. From Dickinson et al., Ref. .
Figure 12. Figure 12. Effect of salt on eNOS activity in bovine aortic endothelial cells. Cells were incubated with [3H] l‐arginine in PBS buffer containing 137, 142, 147, and 150 mmol/L NaCl. From Li et al., Ref. .
Figure 13. Figure 13. Scheme defining the role of extracellular sodium in the regulation of vascular tone. Sodium enters the endothelial cell through ENaC. After a transient increase in cell volume, the endothelial cell membrane stiffens. This renders the cell less sensitive to shear stress, and therefore reduces shear‐dependent NO synthesis and release. From Oberleithner et al., Ref. .
Figure 14. Figure 14. Mechanisms of protective effect of low dose ANG II infusion to restore endothelial function and vascular relaxation mechanisms in animals fed high‐salt diet. Based on McEwen et al., Ref. and Weber and Lombard, Ref. .
Figure 15. Figure 15. Structural degeneration of cremaster muscle arterioles in regions of the same RRM rat fed high‐salt diet for 3 days. (Top panel) Normal arteriole. (Bottom panel) Structural degeneration of cremasteric arteriole in high‐salt‐fed RRM rat. *Vessel lumen. E, endothelial cells; M, smooth muscle cells. Arrowheads—elastin, open triangle—rough endoplasmic reticulum. Scale bar = 1 μm. Note partial or complete loss of basement membranes, separation of endothelial and smooth muscle layers, and increased presence of collagen in the regions underlying the smooth muscle. From Hansen‐Smith et al., Ref. .
Figure 16. Figure 16. Effect of high‐salt diet ± low‐dose ANG II infusion (5 ng/kg/min, i.v.) on microvessel density in cremaster muscle of Sprague‐Dawley rats fed high‐salt diet for 3 days (GS‐1 lectin images‐unpublished) or 4 weeks (histogram—redrawn from Hernandez et al., Ref. ).


Figure 1. Kaplan‐Meier survival curves for normotensive salt‐resistant subjects (N + R), normotensive SS subjects (N + S), hypertensive salt‐resistant subjects (H + R), and hypertensive SS subjects (H + S) over the follow‐up period from initial testing. From Weinberger et al., Ref. .


Figure 2. Flow‐induced dilation of coronary arterioles of normal salt (NS, n‐5, A) and low‐salt (LS, n = 7, B) diet dogs in the control condition and after incubating vessels with apocynin (APO—10−5 M), or apocynin plus Nω‐nitro‐l‐arginine methyl ester (l‐NAME, 3 × 10−4 M) for 30 min. Changes in diameter were normalized to passive diameter (PD) of the vessels. *Significant difference from the curve of APO. From Huang et al., Ref. .


Figure 3. Protein expression of gp91phox and p47phox in coronary arterioles of dogs. Densitometry data were summarized from two blots. *Significant difference from NS dogs. Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH)‐glyceraldehyde‐3‐phosphate dehydrogenase. From Huang et al., Ref. .


Figure 4. Diameter changes to increasing concentrations of ACh in norepinephrine‐precontracted mesenteric arteries from Sprague‐Dawley rats fed either a low‐salt (LS) diet (left; n = 8) or a high‐salt diet (right; n = 8‐9).*P < 0.05 versus precontracted control diameters in the absence of 10−4 M Nω‐Nitro‐l‐arginine methyl ester (l‐NAME). From Raffai et al., Ref. .


Figure 5. DHE staining to indicate superoxide production in mesenteric arteries from rats fed low‐salt diet (A); high‐salt diet (B) and high‐salt diet with tempol in the vessel chamber (C). (D) Summarized data showing changes in the slope of DHE fluorescence intensity during resting conditions in mesenteric arteries from rats fed low‐ and high‐salt diet, with and without tempol in the tissue bath. Data are shown as means ± SEM (n = number of rats).*P < 0.05 versus fluorescence intensity from low salt control; P < 0.05 versus control group on the same diet. From Zhu et al., Ref. .


Figure 6. Arteriolar responses to iontophoretically applied ACh under normal superfusate (A) and a superfusate containing 50 U/mL SOD +50 U/mL catalase in the spinotrapezius muscle of rats fed low‐ (LS) or high‐salt (HS) diet (B) *P < 0.05 versus low salt. P < 0.05 versus high salt at 5 nA; P < 0.05 versus HS at 20 nA. From Lenda et al., Ref. .


Figure 7. Effect of apocynin (100 μmol/L) and oxipurinol (100 μmol/L) on the basal level of NO production, evaluated as the slope ratio of DAF‐2T fluorescence intensity in mesenteric resistance arteries from rats fed high‐ or low‐salt diet. Data are shown as means ± SEM, and n = number of rats. *P < 0.05 versus corresponding vessels from rats fed low‐salt diet; P < 0.05 versus untreated control. Replotted from Zhu et al., Ref. .


Figure 8. (Top) Arteriolar wall BH4 content in mice fed normal salt or high‐salt diet, with or without l‐arginine (l‐ARG) supplementation. *P < 0.05 versus untreated and L‐ARG supplemented normal salt. (Bottom) Magnitude of responses to ACh, under normal superfusate (control) and in the presence of Nω‐nitro‐l‐arginine methyl ester (l‐NAME), in mice fed normal‐ or high‐salt diet, with or without l‐arginine supplementation. P < 0.05 versus control. Replotted from Nurkiewicz et al., Ref. .


Figure 9. Afferent arteriolar diameter in response to changing renal perfusion pressure in kidney using the in vitro juxtamedullary nephron technique. Responses of normal salt (NS), high salt (HS), normal salt plus apocynin (Apo), and high salt plus Apo groups are expressed as a percentage of the control diameter. The autoregulatory profile ranged from 65 to 170 mmHg. *P < 0.05, high‐salt versus normal‐salt groups; P < 0.05, high salt versus high salt plus APO groups. From Fellner et al., Ref. .


Figure 10. Brachial artery flow‐mediated dilation (FMD) for men (white bars) and women (black bars) after low‐salt (LS) and high‐salt (HS) diet. *P < 0.05 compared to respective low salt; P < 0.05 compared to men on high salt. From Lennon‐Edwards et al., Ref. .


Figure 11. Brachial artery flow‐mediated dilation (FMD) at fasting (time 0) and in response to consumption of a low‐salt meal and a high‐salt meal. n = 16 (10 women and 6 men). *Significantly different from the high‐salt meal, P < 0.01. From Dickinson et al., Ref. .


Figure 12. Effect of salt on eNOS activity in bovine aortic endothelial cells. Cells were incubated with [3H] l‐arginine in PBS buffer containing 137, 142, 147, and 150 mmol/L NaCl. From Li et al., Ref. .


Figure 13. Scheme defining the role of extracellular sodium in the regulation of vascular tone. Sodium enters the endothelial cell through ENaC. After a transient increase in cell volume, the endothelial cell membrane stiffens. This renders the cell less sensitive to shear stress, and therefore reduces shear‐dependent NO synthesis and release. From Oberleithner et al., Ref. .


Figure 14. Mechanisms of protective effect of low dose ANG II infusion to restore endothelial function and vascular relaxation mechanisms in animals fed high‐salt diet. Based on McEwen et al., Ref. and Weber and Lombard, Ref. .


Figure 15. Structural degeneration of cremaster muscle arterioles in regions of the same RRM rat fed high‐salt diet for 3 days. (Top panel) Normal arteriole. (Bottom panel) Structural degeneration of cremasteric arteriole in high‐salt‐fed RRM rat. *Vessel lumen. E, endothelial cells; M, smooth muscle cells. Arrowheads—elastin, open triangle—rough endoplasmic reticulum. Scale bar = 1 μm. Note partial or complete loss of basement membranes, separation of endothelial and smooth muscle layers, and increased presence of collagen in the regions underlying the smooth muscle. From Hansen‐Smith et al., Ref. .


Figure 16. Effect of high‐salt diet ± low‐dose ANG II infusion (5 ng/kg/min, i.v.) on microvessel density in cremaster muscle of Sprague‐Dawley rats fed high‐salt diet for 3 days (GS‐1 lectin images‐unpublished) or 4 weeks (histogram—redrawn from Hernandez et al., Ref. ).
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Matthew A. Boegehold, Ines Drenjancevic, Julian H. Lombard. Salt, Angiotensin II, Superoxide, and Endothelial Function. Compr Physiol 2015, 6: 215-254. doi: 10.1002/cphy.c150008