AVE 0991, a Nonpeptide Mimic of the Effects of Angiotensin-(1–7) on the Endothelium

Abstract

Abstract-Recently, we demonstrated that the heptapeptide angiotensin-(1-7) (Ang- [1][2][3][4][5][6][7]) exhibits a favorable kinetic of nitric oxide (NO) release accompanied by extremely low superoxide (O 2 Ϫ ) production. In this report we describe AVE 0991, a novel nonpeptide compound that evoked effects similar to Ang-(1-7) on the endothelium. AVE 0991 and unlabeled Ang-(1-7) competed for high-affinity binding of [125 I]-Ang-(1-7) to bovine aortic endothelial cell membranes with IC 50 values of 21Ϯ35 and 220Ϯ280 nmol/L, respectively. Stimulated NO and O 2 Ϫ release from bovine aortic endothelial cells was directly and simultaneously measured on the cell surface by selective electrochemical nanosensors. Peak concentrations of NO and O 2 Ϫ release by AVE 0991 and Ang-(1-7) (both 10 mol/L) were not significantly different (NO: 295Ϯ20 and 270Ϯ25 nmol/L; O 2 Ϫ : 18Ϯ2 and 20Ϯ4 nmol/L). However, the released amount of bioactive NO was Ϸ5 times higher for AVE 0991 in comparison to Ang-(1-7). The selective Ang-(1-7) antagonist [D-Ala 7 ]-Ang-(1-7) inhibited the AVE 0991-induced NO and O 2 Ϫ production by Ϸ50%. A similar inhibition level was observed for the Ang II AT 1 receptor antagonist EXP 3174. In contrast, the Ang II AT 2 receptor antagonist PD 123,177 inhibited the AVE 0991-stimulated NO production by Ϸ90% but without any inhibitory effect on O 2 Ϫ production. Both NO and O 2 Ϫ production were inhibited by NO synthase inhibition (Ϸ70%) and by bradykinin B 2 receptor blockade (Ϸ80%). AVE 0991 efficiently mimics the effects of Ang-(1-7) on the endothelium, most probably through stimulation of a specific, endothelial Ang-(1-7)-sensitive binding site causing kinin-mediated activation of endothelial NO synthase.

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…In addition, Ang-(1-7) immunoreactivity was significantly increased in the tissue surrounding the infarct area of rat hearts with myocardial infarction (Averill et al 2003). Wiemer et al (2002) published the first study demonstrating that the compound AVE 0991 is a nonpeptide and orally active Ang-(1-7) receptor agonist that mimics the Ang-(1-7) effects in bovine endothelial cells. Pinheiro et al (2004) and Lemos et al (2005) reported that this compound acts as a Mas agonist in the kidney and isolated aortic rings respectively.…”

Anti-Inflammatory Effects of the Activation of the Angiotensin-(1–7) Receptor, Mas, in Experimental Models of Arthritis

“…Several in vivo and in vitro studies have demonstrated that this receptor binds Ang-(1-7) and is involved in the biologic actions of this heptapeptide (18). Another important tool for studying the interaction of Ang-(1-7) and its Mas receptor is the compound AVE 0991 (22). This compound is a nonpeptide and an orally active Ang-(1-7) Mas receptor agonist that mimics the effects of Ang-(1-7) in several organs, including blood vessels (23,24), kidneys (25), and the heart (26).…”

Renin-angiotensin system in the kidney: What is new?

“…The difficulty was overcome after the synthesis of the first nonpeptide compound able to mimic Ang-(1-7) and bind selectively to the Mas receptor [136] , the AVE 0991 5-formyl-4-methoxy-2-phenyl-1-{[4-(2-ethyl-ami- nocarbonylsulfonamido-5-isobutyl-3-thienyl)-phenyl]-me thyl}-imidazole (Table 2) [137] . Although this molecule is an antihypertensive candidate because it stimulates NO release in endothelial cells [137] , promotes vasorelaxation in mouse and rat aortic rings [138] , and attenuates hypertension in SHR [139] , clinical trials are needed to see its effects in humans.…”

“…Although this molecule is an antihypertensive candidate because it stimulates NO release in endothelial cells [137] , promotes vasorelaxation in mouse and rat aortic rings [138] , and attenuates hypertension in SHR [139] , clinical trials are needed to see its effects in humans.…”