Lemos Virginia S, Silva Denise M R, Walther Thomas, Alenina Natalia, Bader Michael, Santos Robson A S
Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil, and Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University, Berlin, Germany.
J Cardiovasc Pharmacol. 2005 Sep;46(3):274-9. doi: 10.1097/01.fjc.0000175237.41573.63.
Recently, we demonstrated that the endothelium-dependent vasodilator effect of angiotensin(1-7) in the mouse aorta is abolished by genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene. To circumvent the limitations posed by the possible metabolism of Ang(1-7) in this vessel, in this work we studied the mechanism underlying the vasorelaxant effect of AVE 0991, a nonpeptide mimic of the effects of Ang(1-7), using wild-type and Mas-deficient mice. Ang(1-7) and AVE 0991 induced an equipotent concentration-dependent vasodilator effect in aortic rings from wild-type mice that was dependent on the presence of endothelium. The vasodilator effect of Ang(1-7) and AVE 0991 was completely blocked by 2 specific Ang(1-7) receptor antagonists, A-779 and D-Pro-Ang(1-7), and by inhibition of NO synthase with L-NAME. Moreover, in aortic rings from Mas-deficient mice, the vasodilator effect of both Ang(1-7) and AVE 0991 was abolished. In contrast, the vasodilator effect of acetylcholine and substance P were preserved in Mas-null mice. In addition, the vasoconstriction effect induced by Ang II was slightly increased, and the vasodilation induced by the AT2 agonist CGP 42112A was not altered in Mas-deficient mice. Our results show that Ang(1-7) and AVE 0991 produced an NO-dependent vasodilator effect in the mouse aorta that is mediated by the G protein-coupled receptor Mas.
最近，我们证明，在小鼠主动脉中，血管紧张素（1-7）的内皮依赖性血管舒张作用会因原癌基因Mas编码的G蛋白偶联受体的基因缺失而被消除。为了规避该血管中血管紧张素（1-7）可能的代谢所带来的局限性，在本研究中，我们使用野生型和Mas基因缺陷型小鼠，研究了AVE 0991（一种血管紧张素（1-7）效应的非肽模拟物）血管舒张作用的潜在机制。血管紧张素（1-7）和AVE 0991在野生型小鼠的主动脉环中诱导出等效的浓度依赖性血管舒张作用，该作用依赖于内皮的存在。血管紧张素（1-7）和AVE 0991的血管舒张作用被两种特异性血管紧张素（1-7）受体拮抗剂A-779和D-脯氨酸-血管紧张素（1-7）以及用L-NAME抑制一氧化氮合酶完全阻断。此外，在Mas基因缺陷型小鼠的主动脉环中，血管紧张素（1-7）和AVE 0991的血管舒张作用均被消除。相比之下，乙酰胆碱和P物质的血管舒张作用在Mas基因敲除小鼠中得以保留。此外，血管紧张素II诱导的血管收缩作用略有增加，而AT2激动剂CGP 42112A诱导的血管舒张作用在Mas基因缺陷型小鼠中未发生改变。我们的结果表明，血管紧张素（1-7）和AVE 0991在小鼠主动脉中产生了一种由G蛋白偶联受体Mas介导的、依赖一氧化氮的血管舒张作用。
