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There is increasing evidence for the importance of rapid nongenomic effects of aldosterone on the human vasculature. In vitro animal experiments in renal arterioles also suggest the presence of such effects on the renal vasculature. We conducted a clinical study to explore these effects in vivo in humans. Thirteen healthy male volunteers were examined. Aldosterone (500 μg) or placebo was injected intravenously with or without coinfusion of N(G) monomethyl -l- arginine ( l -NMMA) in a randomized, double-blinded 4-fold crossover design. Renal plasma flow and glomerular filtration rate were measured by constant infusion clearance technique using inulin and para -aminohippuric acid. Injection of aldosterone without concomitant infusion of l -NMMA changed the renal plasma flow and glomerular filtration rate not statistically significant compared with placebo. Coinfusion of l -NMMA unmasked the effect of aldosterone: aldosterone with l -NMMA decreased the glomerular filtration rate slightly (−1.4±6.2 mL/min), whereas infusion of l -NMMA alone increased the glomerular filtration rate (8.3±9.8 mL/min; P =0.004). l -NMMA alone decreased renal plasma flow by 58.2±97.5 mL/min, and aldosterone with l -NMMA decreased renal plasma flow by 190.0±213.7 mL/min ( P =0.074). Accordingly, Aldosterone with l -NMMA increased renal vascular resistance much more than l -NMMA alone (1588±237 versus 614±240 dyn×s×cm −5 ; P =0.014). These data indicate that aldosterone acts via rapid nongenomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial NO synthase unmasks these effects. Therefore, rapid nongenomic aldosterone effects increase renal vascular resistance and thereby mediate arterial hypertension if endothelial dysfunction is present.

BACKGROUND Reactive oxygen species play a major role in the development of endothelial dysfunction. It is as yet unspecified whether increased oxidative stress contributes to endothelial dysfunction of the renal vasculature in patients with type 2 diabetes. METHODS Renal haemodynamics were studied in 20 patients with type 2 diabetes and arterial hypertension (age 62 +/- 5 years) and 20 non-diabetic hypertensive patients at baseline and following infusions of the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg); the substrate of nitric oxide synthase, L-arginine (100 mg/kg); and the antioxidant, vitamin C (3 g, co-infused with L-arginine 100 mg/kg). RESULTS The response of renal plasma flow (RPF) to L-NMMA (-54 +/- 62 and -45 +/- 42 ml/min/1.73 m(2); P = NS) and L-arginine (+46 +/- 36 and +49 +/- 25 ml/min/1.73 m(2); P = NS) was not different between diabetic and non-diabetic patients. In contrast, vitamin C induced a more pronounced increase in RPF in diabetic than in non-diabetic patients when co-infused with L-arginine (+71+/-47 and +43+/-33 ml/min/1.73 m(2); P

Effects of enalapril and eprosartan on the renal vascular nitric oxide system in human essential hypertension. Background Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension. Methods Twenty male, white patients (27 ± 1 years) with mild essential hypertension (143 ± 11/95 ± 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with N G -monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). Results After one week of therapy, the combination therapy decreased casual blood pressure by 5 ± 2/3 ± 1 mm Hg versus placebo ( P !0.01). Neither enalapril alone (-2 ± 2/1 ± 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 ± 1/0 ± 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 ± 36 mL/min ( P !0.01). Neither enalapril alone (+59 ± 46 mL/min, P = 0.21) nor eprosartan alone (+113 ± 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination ( r = 0.70, P !0.01) and eprosartan phase ( r = 0.86, P !0.001), but not in the enalapril phase ( r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment. Conclusions In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.

Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension.Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg).After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P0.01) and eprosartan phase (r = 0.86, P0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment.In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.

Systemic administration of L-arginine alters renal haemodynamics in humans. We examined whether L-arginine-induced vasodilation of the renal vasculature is related to an increased production and release of NO by comparing the effects of L- and D-arginine on renal endothelium-dependent vasodilation. In a double-blind randomized cross-over study including 20 young, healthy male white subjects (age 26±2 years), we determined the effects of intravenous administration of L-arginine or its enantiomer D-arginine, at doses of 100 mg/kg body weight for 30 min or 500 mg/kg for 30 min, on renal haemodynamics. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by a constant-infusion input-clearance technique (using p-aminohippuric acid and inulin respectively). In addition, changes in blood pressure, heart rate, urinary sodium excretion (UNa) and urinary cGMP were measured. HPLC was used to determine L- and D-arginine concentrations. Intravenous infusion of L-arginine at 100 mg/kg for 30 min increased RPF from 641±87 to 677±98 ml/min (P = 0.019), whereas infusion of D-arginine did not (from 642±74 to 657±86 ml/min; not significant). The change in RPF was more marked during the infusion of L-arginine than during the infusion of D-arginine (+36±61 versus +16±57 ml/min; P = 0.037). Infusion of both L- and D-arginine at doses of 500 mg/kg for 30 min increased RPF from baseline [from 641±87 to 762±133 ml/min (P < 0.001) and from 642±74 to 713±120 ml/min (P = 0.004) respectively], but the change in RPF again was greater in response to L-arginine infusion than to infusion with D-arginine (+121±97 versus +71±94 ml/min; P = 0.018). In accordance, changes in renal vascular resistance (RVR) were higher in response to L-arginine compared with D-arginine for both doses (P < 0.05 and P< 0.001 respectively). UNa increased only with L-arginine (change in UNa, +0.33±0.26 mmol/min; P< 0.01) but not with D-arginine (change in UNa, +0.11±0.17 mmol/min; not significant). The change in UNa was more pronounced during infusion of L-arginine compared with infusion of D-arginine (P = 0.023). In parallel, urinary excretion of cGMP only increased in response to L-arginine (+676±272 pmol/l; P = 0.038) and not during D-arginine infusion (+185±153 pmol/l; not significant). L-Arginine-induced changes in RPF, RVR, UNa and cGMP excretion differed significantly from those induced by D-arginine. Thus although no direct measurements of NO synthesis were performed, putative markers of NO synthesis suggest that the renal vasodilatory response to L-arginine, at least in part, was due to increased production and release of NO. The dose of L-arginine at 100 mg/kg for 30 min emerged as the most suitable, because of the absence of systemic haemodynamic changes. The effects of infusion of L-arginine at 500 mg/kg for 30 min on renal endothelium-dependent vasodilation need to be corrected for the effects of D-arginine before conclusions can be drawn.