Angiotensin-(1-7) Dilates Canine Coronary Arteries Through Kinins and Nitric Oxide

Abstract

Abstract 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% CO 2 at 37°C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73±0.58 μmol/L, EC 50 ) of rings precontracted with the thromboxane A 2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N ω -nitro- l -arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 μmol/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 μmol/L) or by 80% with the nonselective Ang II antagonist [Sar 1 ,Thr 8 ]-Ang II (1 μmol/L). In contrast, the selective AT 1 or AT 2 Ang II antagonists CV 11974 (1 μmol/L) and PD 123319 (1 μmol/L), respectively, were ineffective in inhibiting the Ang-(1-7)–elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 μmol/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 long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.