Carvalho Mariana B L, Duarte Fernanda V, Faria-Silva Raphael, Fauler Beatrix, da Mata Machado Leonor T, de Paula Renata D, Campagnole-Santos Maria J, Santos Robson A S
Laboratory of Hypertension, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Hypertension. 2007 Oct;50(4):762-7. doi: 10.1161/HYPERTENSIONAHA.107.094987. Epub 2007 Jul 30.
We evaluated the effect of the nonpeptide mimic of angiotensin (Ang)-(1-7), AVE 0991, on the hypotensive effect of bradykinin (BK). Increasing doses of intra-arterial or intravenous BK were administered before and 30 minutes after the beginning of AVE 0991 infusion. The effect of AVE 0991 on plasma Ang-converting enzyme activity was tested using Hip-His-Leu as the substrate. The interaction of AVE 0991 with Ang-converting enzyme in vivo was tested by determining its effect on the pressor action of Ang I or Ang II. AVE 0991 produced a significant and similar potentiation of intra-arterial or intravenous bradykinin. AVE 0991 did not inhibit plasma Ang-converting enzyme activity in vitro or the pressor effect of Ang I in vivo. N(W)-nitro-l-arginine methyl ester or D-Ala(7)-Ang-(1-7) administration abolished the BK potentiating effect of AVE 0991. We further examined the BK-potentiating effect of AVE 0991, evaluating its effect on NO production in rabbit endothelial cells. The NO release was measured using the 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate. A synergistic effect of AVE 0991 and BK on NO release was observed. These results suggest that AVE 0991 potentiates bradykinin through an Ang-converting enzyme-independent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo.
我们评估了血管紧张素（Ang）-(1-7)的非肽模拟物AVE 0991对缓激肽（BK）降压作用的影响。在开始输注AVE 0991之前及之后30分钟，分别给予递增剂量的动脉内或静脉内BK。以Hip-His-Leu为底物，检测AVE 0991对血浆血管紧张素转换酶活性的影响。通过测定AVE 0991对Ang I或Ang II升压作用的影响，检测其在体内与血管紧张素转换酶的相互作用。AVE 0991对动脉内或静脉内缓激肽产生了显著且相似的增强作用。AVE 0991在体外不抑制血浆血管紧张素转换酶活性，在体内也不抑制Ang I的升压作用。给予N（W）-硝基-L-精氨酸甲酯或D-Ala(7)-Ang-(1-7)可消除AVE 0991对BK的增强作用。我们进一步研究了AVE 0991增强BK的作用，评估其对兔内皮细胞一氧化氮（NO）生成的影响。使用4-氨基-5-甲基氨基-2'-7'-二氟荧光素二乙酸酯测量NO释放。观察到AVE 0991和BK对NO释放具有协同作用。这些结果表明，AVE 0991通过一种不依赖血管紧张素转换酶、依赖NO的受体Mas介导的机制增强缓激肽。这种作用可能有助于AVE 0991在体内改善内皮功能。
