Impaired endothelial function of the retinal vasculature in hypertensive patients

<p><b>Background and Purpose:</b> Arterial hypertension constitutes a central factor in the pathogenesis of stroke. We examined endothelial function of the retinal vasculature as a model of the cerebral circulation.</p> <p><b>Methods:</b> Thirty-eight young subjects (19 hypertensive and 19 normotensive) were treated with the AT1-receptor blocker candesartan cilexetil and placebo, each over 7 days. Retinal capillary flow and blood flow velocity in the central retinal artery were assessed with scanning laser Doppler flowmetry and pulsed Doppler ultrasound, respectively. NG-monomethyl-L-arginine (L-NMMA) was infused to inhibit nitric oxide (NO) synthesis. Diffuse luminance flicker was applied to stimulate NO release.</p> <p><b>Results:</b> In normotensive subjects, L-NMMA decreased retinal capillary flow by 8.2%±13% (P<0.05) and flickering light increased mean blood flow velocity in the central retinal artery by 19%±29% (P<0.01). In contrast, no significant change to these provocative tests was seen in hypertensive subjects. Treatment with candesartan cilexetil restored a normal pattern of reactivity in retinal capillaries (L-NMMA: decrease in perfusion by 10%±17%, P<0.05) and the central retinal artery (flicker: increase in mean blood flow velocity by 42%±31%, P<0.001) in hypertensive patients.</p> <p><b>Conclusions:</b> Endothelial function of the retinal vasculature is impaired in early essential hypertension but can be improved by AT1-receptor blockade.</p&gt

Effects of nitric oxide synthase inhibition and L-arginine on renal haemodynamics in young patients at high cardiovascular risk

<p><b>Background:</b> Aging and a variety of cardiovascular risk factors are associated with oxidative stress and impaired endothelial function. Whether such an association is already evident in the renal vascular bed in young patients at high cardiovascular risk has not yet been determined.</p> <p><b>Methods:</b> We compared renal haemodynamics in 23 young (age 30 ± 5 years) male patients at high cardiovascular risk with impaired lipid metabolism and elevated blood pressure with 23 matched, healthy control subjects (age 28 ± 3 years) without cardiovascular risk factors at baseline and following infusions of the nitric oxide (NO) synthase inhibitor NG-monomethyl-l-arginine (l-NMMA: 4.25 mg/kg), the substrate of NO synthase l-arginine (100 mg/kg) and the antioxidant Vitamin C (3 g, co-infused with l-arginine 100 mg/kg).</p> <p><b>Results:</b> Baseline renal haemodynamics did not differ between the two groups. Infusion of l-NMMA decreased renal plasma flow (RPF) in both groups to a similar extent (−113 ± 95 ml/min versus −128 ± 133 ml/min, p = NS). The response of RPF to infusion of l-arginine was more pronounced in high risk patients than in control subjects (+123 ± 64.4 ml/min versus +75.6 ± 60.2 ml/min, p = 0.012) and further exaggerated during co-infusion of l-arginine and Vitamin C (+299 ± 164 ml/min versus +175 ± 148 ml/min, p = 0.003).</p> <p><b>Conclusions:</b> Basal NO activity of the renal vasculature appears to be unaltered in young patients at high cardiovascular risk. However, the greater response of RPF to l-arginine and to Vitamin C co-infused with l-arginine in these young patients suggests that decreased substrate availability for NO synthase and oxidative stress are key factors for alterations in endothelium-dependent vasodilation of the renal vasculature in this young high risk group of patients.</p&gt

Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension

<p><b>Background:</b> It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension.</p> <p><b>Methods:</b> In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 g/min and 3.2 and 12.8 g/min, respectively.</p> <p><b>Results:</b> Subjects with essential hypertension had impaired responses to both doses of Ach (% FBF to higher dose of Ach: 325 146 in subjects with essential hypertension v 540 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 108 v 500 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 146 without v 338 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 132 without v 400 185 with VITC, P = .05) and to NP (383 162 v 447 170, P = .05).</p> <p><b>Conclusions:</b> We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.</p&gt

L-arginine-induced vasodilation of the renal vasculature is not altered in hypertensive patients with type 2 diabetes

<p>OBJECTIVE: Diabetes, arterial hypertension, hypercholesterolemia, and aging are associated with endothelial dysfunction in various vasculatures. Endothelium-dependent vasodilation of the renal vasculature cannot be easily assessed, but infusion of l-arginine, the substrate of endothelial nitric oxide synthase, leads to an increase in renal plasma flow (RPF) in humans. We have examined the effect of l-arginine infusion on renal hemodynamics in hypertensive patients with type 2 diabetes.</p> <p>RESEARCH DESIGN AND METHODS: Twenty-three elderly patients with type 2 diabetes (age, 65 ± 6 years; HbA1c, 7.8 ± 1.6%) with coexisting arterial hypertension (158 ± 19/83 ± 11 mmHg) and elevated cholesterol levels (total cholesterol, 215 ± 33 mg/dl) were examined. These patients were compared with a young and healthy reference group (n = 20; age, 26 ± 2 years). The effect of l-arginine infusion (100 mg/kg over 30 min) on RPF and glomerular filtration rate were measured using the constant input clearance technique with p-aminohippurate and inulin, respectively.</p> <p>RESULTS: l-Arginine infusion similarly influenced renal hemodynamics in patients and reference subjects: RPF increased by 7 ± 11 and 7 ± 11% in diabetic and reference subjects, respectively (P = NS). Other parameters of renal hemodynamics such as glomerular filtration rate (5 ± 5 vs. 4 ± 4%) and filtration fraction (−1 ± 8 vs. −1 ± 9%) were not significantly different between diabetic and reference subjects, too.</p> <p>CONCLUSIONS: l-Arginine-induced vasodilation of the renal vasculature is not different between a group of hypertensive diabetic patients and a young, healthy reference group. These data were obtained using low-dose l-arginine infusion.</p&gt

The C242T p22phox polymorphism and endothelium-dependent vasodilation in subjects with hypercholesterolaemia

Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratifed for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. NG-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n=90 had a power of >80% (b=0.20) with a P value of <0.05 (a=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia