ABSTRACT
BACKGROUND: It has been clearly demonstrated that angiotensin(1-7) potentiates the vasodilating effect of bradykinin in isolated vessels of animals. OBJECTIVE: To investigate the interaction between angiotensin(1-7) Ang(1-7) and bradykinin in human forearm resistant vessels of normotensive healthy men in vivo, by the measurement of forearm blood flow using venous occlusion, strain-gauge plethysmography with intra-arterial infusions of peptides in a placebo-controlled, double-blind, cross-over design. METHODS: In eight men, bradykinin was infused intra-arterially twice; placebo, Ang(1-7), or angiotensin II was co-infused with the second infusion. The effect of inhibition of nitric oxide synthase on the interaction between Ang(1-7) and bradykinin was also tested in eight other individuals. The effects of Ang(1-7) were analyzed by analysis of variance (ANOVA) and by the ratios of individually derived areas under the dose-response curves (AUC) of bradykinin, adjusted for changes in the AUCs by repeated infusions of bradykinin with placebo. RESULTS: Ang(1-7) (1000 pmol/min) significantly potentiated the vasodilating effect of bradykinin compared with the effect of saline (P = 0.0471, ANOVA) and in a dose-dependent manner (adjusted AUC ratio [95% confidence interval (CI)] 2.75 (1.72 to 3.78) with 1000 pmol/min, 1.62 (1.31 to 1.93) with 100 pmol/min, and 0.98 (0.80, to 1.09) with 10 pmol/min). This effect was completely abolished by co-infusion of NG-monomethyl-l-arginine [AUC ratio 0.98 (0.90 to 1.04)]. Ang(1-7) did not affect the vasodilating effects of either acetylcholine or sodium nitroprusside. CONCLUSIONS: Ang(1-7) potentiates the vasodilating effect of bradykinin, possibly through a mechanism(s) involving nitric oxide release, in human forearm resistance vessels.
Subject(s)
Angiotensin I/pharmacology , Bradykinin/pharmacology , Peptide Fragments/pharmacology , Vasodilation/drug effects , Adult , Angiotensin I/administration & dosage , Angiotensin II/pharmacology , Bradykinin/administration & dosage , Cross-Over Studies , Double-Blind Method , Drug Synergism , Enzyme Inhibitors/pharmacology , Humans , Male , Peptide Fragments/administration & dosage , Reference Values , Vasoconstrictor Agents/pharmacology , omega-N-Methylarginine/pharmacologyABSTRACT
Angiotensin-(1-7) has been suggested to be a novel vasodilating peptide. We investigated the direct vascular effect of angiotensin-(1-7) in human forearm resistant vessels, particularly with regard to the interaction with angiotensin II, in healthy normotensive men by strain-gauge venous occlusion plethysmography with intra-arterial infusions of peptides. Intra-arterial infusion of angiotensin-(1-7) at 0.1 to 2000 pmol/min did not cause vasodilatation but rather reduced forearm blood flow by approximately 10% at the highest dose. A placebo-controlled study showed that angiotensin-(1-7) at 0.5 to 40 nmol/min caused weak but significant vasoconstriction (P=0.0016 by ANOVA). Angiotensin-(1-7) at 100 pmol/min, but not at 10 pmol/min, significantly shifted the angiotensin II dose-response curve toward the right (mean+/-SD of percent changes in forearm blood flow: -19+/-17%, -33+/-22%, -55+/-12%, -63+/-10%, and -68+/-5% at 5, 10, 25, 50, and 100 pmol/min of angiotensin II, respectively, with saline; 5+/-13%, 0. 9+/-18%, -40+/-16%, -54+/-9%, and -61+/-6% with angiotensin-(1-7), P=0.0021 by ANOVA). Angiotensin-(1-7) did not affect the dose-response curve of noradrenaline [3+/-12%, 5+/-16%, -20+/-22%, -31+/-18%, and -40+/-12% at 25, 50, 100, 300, and 600 pmol/min of noradrenaline, respectively, with saline; -4+/-15%, -2+/-23%, -29+/-22%, -34+/-16%, and -42+/-9% with angiotensin-(1-7)]. Our results suggest that angiotensin-(1-7) antagonizes vasoconstriction by angiotensin II in human resistant vessels and might act as an endogenous angiotensin II antagonist.
