Angiotensin-(1-7): a novel vasodilator of the coronary circulation

Angiotensin-(1-7) [Ang-(1-7)] possesses novel biological functions that are distinct from angiotensin II (Ang II). In coronary arteries, the octapeptide Ang II and the heptapeptide Ang-(1-7) exert opposing actions, Ang II elicits vasoconstriction and Ang-(1-7) is a vasodilator. Ang-(1-7) elicits vasodilation by an endothelium-dependent release of nitric oxide. Further; the vasorelaxant activity is markedly attenuated by the bradykinin (BK) Bz receptor antagonist icatibant and does not appear to be associated with the synthesis and release of prostaglandins. Ang-(1-7) vasodilation is mediated by a non-AT(1)/AT(2) receptor, since [Sar(1)Thr(8)]-Ang II, but neither candesartan, an AT(1) receptor antagonist, nor PD123319, an AT(2) receptor antagonist, blocked the response. Specific and high affinity binding of (125)1-Ang-(1-7) to the endothelial layer of canine coronary arteries was demonstrated using in vitro emulsion autoradiography. Binding was effectively competed for by either unlabeled Ang-(1-7) or the specific Ang-(1-7) antagonist [D-Ala(7)]-Ang-(1-7). Additionally, Ang-(1-7) potentiated synergistically BK-induced vasodilation. The ECS, of BK vasodilation (2.45 +/- 0.51 nmol/L vs 0.37 +/- 0.08 nmol/L) was shifted 6.6-fold left-ward in the presence of 2 mu mol/L concentration of Ang-(1-7). The potentiated response was specific for BK, since Ang-(1-7) did not augment the vasodilation produced by either acetylcholine or sodium nitroprusside; further, it was specific for Ang-(1-7), since neither Ang I nor Ang II augmented the BK response. In contrast to the vasodilator actions of Ang-(1-7), the potentiated response was not blocked by candesartan, PD123319 or [Sar(1)Thr(8)Y]-Ang II. Novel studies from our group demonstrate that Ang-(1-7) is both a substrate and inhibitor for angiotensin converting enzyme (ACE). Ang-(1-7) was shown to retard the degradation of I-125-[Tyr(0)]-BK in coronary rings. These studies describe novel actions of Ang-(1-7) as a vasodilator and a local synergistic modulator of kinin-induced vasodilation in coronary arteries.