Effect of angiotensin II infusion with and without angiotensin II type 1 receptor blockade on nitric oxide metabolism and endothelin in human beings:A placebo-controlled study in healthy volunteers

Background: Angiotensin II has been shown to induce the synthesis of endoth elium-derived relaxing factor nitric oxide (NO) and endothelin in vitro. In human beings, to our knowledge, no data on NO release in response to angio tensin II and on the influence of angiotensin II type 1 receptor blockade h ave been published. Methods: In a placebo-controlled study in nine healthy volunteers, angioten sin II was administered intravenously for 6 hours with and without pretreat ment with valsartan, a specific angiotensin II type 1 receptor antagonist. NO (NO2 + NO3) and endothelin plasma concentrations, clearance values for i nulin and paraaminohippuric acid and NO (NO2 + NO3) excretion in urine were determined. Results: During angiotensin II infusion NO plasma concentrations remained u naltered compared with placebo after 3 hours: 6.66 +/- 5.49 versus 5.56 +/- 3.09 mu mol/L (P = ns) but increased after 6 hours: 18.36 +/- 20.02 versus 7.13 +/- 3.87 mu mol/L (P < .04). The same was noted after pretreatment wi th valsartan: 7.61 +/- 5.69 versus 5.56 +/- 3.09 mu mol/L (P = ns) after 3 hours, and 21.70 +/- 11.51 versus 7.13 +/- 3.87 mu mol/L (P = .02) after 6 hours. In urine fractional NO excretion decreased after angiotensin II infu sion: 0.87 +/- 0.72 versus 0.95 +/- 0.71 (P = .5) during the first 3 hours, and 0.44 +/- 0.39 versus 0.78 +/- 0.43 (P = .01) during the following 3 ho urs. After valsartan pretreatment the decrease in fractional urinary NO exc retion began earlier: 0.40 +/- 0.15 versus 0.95 +/- 0.71 (P = .04) during t he first 3 hours, and 0.17 +/- 0.11 versus 0.78 +/- 0.43 (P = .01) during t he following 3 hours. Endothelin plasma concentrations showed no difference after angiotensin n infusion with or without valsartan. Conclusions: Our observations demonstrate for the first time that angiotens in II increases NO plasma concentrations in human beings and that this resp onse is not mediated by angiotensin II type 1 receptor. In spite of increas ed NO plasma levels, urinary NO excretion decreased. Endothelin plasma leve ls remained unchanged during angiotensin II infusion. (Clin Pharmacol Ther 2000;68:501-9.).