Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O-2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73+/-0.58 mu mol/L, EC(50)) of rings precontracted with the U46,619. Pretreatment with the nitric oxide synthase inhibitor N-omega-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 mu mol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B-2 receptor antagonist Hoe 140 (1 mu mol/L) or by 80% with the nonselective Ang II antagonist [Sar(1),Thr(8)]-Ang II (1 mu mol/L). In contrast, the selective AT(1) or AT(2) Ang II antagonists CV 11974 (1 mu mol/L) and PD 123319 (1 mu mol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 mu mol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B-2 bradykinin receptor and a non-AT(1), non-AT(2) angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying longterm administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.