Effects of angiotensin II type 1-receptor blockade on retinal endothelial function.

OBJECTIVE: Hypercholesterolemia is an important risk factor for atherosclerotic vascular disease including stroke. Low-density lipoprotein-cholesterol may induce upregulation of angiotensin II type 1 (AT1)-receptors and their activation plays a pathogenetic role in atherosclerosis, possibly via enhanced breakdown of nitric oxide. We tested whether AT1-receptor blockade improved endothelial function of the retinal vasculature in normocholesterolemic and hypercholesterolemic subjects. METHODS: Thirty-one hypercholesterolemic and 17 normocholesterolemic subjects were randomly assigned to treatment with irbesartan and placebo in a double-blind crossover study. Retinal capillary flow was measured using scanning laser Doppler flowmetry. Diffuse luminance flicker was applied to provoke vasodilation that is in part nitric oxide dependent. RESULTS: Flicker-induced increases in retinal capillary flow were similar between hypercholesterolemic and normocholesterolemic subjects. In contrast to placebo, treatment with irbesartan led to a significant reduction of blood pressure, in our patients with normal blood pressure values. Therefore we divided our study cohort according to the median blood pressure reduction in response to irbesartan. Flicker-induced increases in retinal capillary flow were substantially higher in subjects with a systolic blood pressure reduction above median (> 6 mmHg) than in those with a reduction below median (

Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans.

BACKGROUND: Experimental data suggest that increased nitric oxide synthase (NOS) activity contributes to preglomerular vasodilation and subsequent glomerular hyperfiltration. Whether such a relationship also exists in the human renal vasculature has not yet been adequately determined. METHODS AND RESULTS: We assessed systemic, renal, and intragomerular haemodynamics in 310 subjects with normal renal function [glomerular filtration rate (GFR) > 60 ml/min per 1.73 m], before and after NOS inhibition with L-Nmonomethyl arginine (L-NMMA). Subjects were arbitrarily divided into tertiles according to their basal NOS activity, as assessed by the decrease in renal plasma flow in response to L-NMMA (high -23.4 +/- 8.1 versus medium -10.8 +/- 2.2 versus low -1.0 +/- 4.8%). Resting GFR differed significantly between tertiles: high 114 +/- 21 versus medium 109 +/- 19 versus low 104 +/- 21 ml/min per 1.73 m; analysis of variance P = 0.003. In a multiple stepwise regression analysis, basal NOS activity was the major factor to explain resting GFR (beta = -0.344; P < 0.001). Body weight (beta = -0.295; P < 0.001) and age (beta = -0.164; P < 0.001) emerged as additional factors, whereas body mass index and blood pressure did not enter the final model. The close relationship between resting GFR and basal NOS activity was also mirrored in the renal microcirculation, as demonstrated by an exaggerated effect of L-NMMA on the increase in arteriolar resistance, particularly that of the afferent (RA) arteriole, with higher basal nitric oxide (NO) activity (RA: high +1542 +/- 1065 versus medium +1024 +/- 718 versus low +675 +/- 861 dyne/s per cm; P < 0.001). CONCLUSION: Our data clearly support experimental evidence linking NOS activity with increased glomerular filtration, and suggest that basal NO activity is also a major determinant of glomerular haemodynamics in the human renal vasculature.