Evidence for Mas-Mediated Bradykinin Potentiation by the Angiotensin-(1-7) Nonpeptide Mimic AVE 0991 in Normotensive Rats

Abstract

Abstract-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-2Ј-7Ј-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 enzymeindependent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo. receptor involved in many of its biological actions 1,2 and of the Ang-converting enzyme (ACE) homologue, ACE 2, as a major Ang-(1-7)-forming enzyme 3,4 gave a more strong support for the concept that Ang-(1-7) is a biologically active component of the renin-Ang system. Furthermore, there is increasing evidence for a role of Ang-(1-7) as a counterregulatory peptide of the cardiovascular effects of Ang II. 2,5 Ang-(1-7) receptor agonists are being considered as putative cardiovascular drugs for the treatment of hypertension, heart failure, atherosclerosis, and many other diseases that involve endothelial dysfunction. 2 Among these compounds AVE 0991, a nonpeptide mimic of Ang-(1-7), 6 has been shown to evoke effects similar to those elicited by Ang-(1-7). 6 -9 In endothelial cells, AVE 0991 releases NO and, to a lesser extent, superoxide. 6 In keeping with the NO-releasing activity of Ang-(1-7) and AVE 0991, 7,8,10 -12 we have shown recently that acute infusion of Ang-(1-7) or AVE 0991 could potentiate the vasodilation produced by intra-arterial acetylcholine, suggesting an improvement of endothelial function. 13 This effect was blocked in the presence of the endothelial NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) or the receptor Mas antagonist D-Ala 7 -Ang-(1-7) (A-779).Bradykinin (BK) is an endogenous peptide that causes vasodilation depending on endothelial factors, such as NO, the endothelium-derived hyperpolarizing factor, or prostaglandins. 14 Ang-(1-7) enhances the effects of BK in a variety of models. [15][16][17][18][19][20] However, Ang-(1-7) does not directly activate the BK B 2 receptor, 12 but it does amp...

Modulation of cardiac L-type Ca2+ current by angiotensin-(1-7): normal versus heart failure

“…Although, the intracellular pathway coupling Ang-(1-7) stimulation is incompletely characterized, it has been reported that an important subset of cardiovascular actions of Ang-(1-7) is related to its BK potentiating activity and its facilitation of NO release [Brosnihan et al 1996; Pinheiro et al 2004; Wiemer et al 2002; Yuill et al 2010]. Mas receptors localized to cardiac myocytes may activate NO production or stimulate BK [Almeida et al 2000; Carvalho et al 2007; Ferreira et al 2001]. Consistent with previous studies, we observed the involvement of the NO and BK pathways in the altered I Ca , L response to Ang-(1-7) in HF.…”

Aerobic Exercise Training–Induced Left Ventricular Hypertrophy Involves Regulatory MicroRNAs, Decreased Angiotensin-Converting Enzyme-Angiotensin II, and Synergistic Regulation of Angiotensin-Converting Enzyme 2-Angiotensin (1-7)

“…Thus the mechanism of aerobic exercise training to prevent LVH could occur by diminished vascular resistance leading to increased cardiac flow, due to the reduction in ACE and Ang II levels and the vasodilator effects of the ACE2-Ang (1–7) expression, mediating the release of different vasoactive factors such as nitric oxide, prostaglandins and bradykinin (40,41). …”

Regulation of angiotensin-converting enzyme 2 and Mas receptor by Ang-(1–7) in heart and kidney of spontaneously hypertensive rats

“…22,23 Rats whose Mas gene was knocked out showed few reactions and beneficial effects when given Ang- (1-7). 24,25 Therefore, connected by Ang- (1-7), a functional axis of ACE2-Ang-(1-7)-Mas was formed. As we know from many past studies about other members of RAS, such as angiotensinogen, renin, Ang II and ACE, inter-regulations between components of RAS are quite common.…”