Recently, we demonstrated that the heptapeptide angiotensin-(1-7) (Ang-[1-7]) exhibits a favorable kinetic of nitric oxide (NO) release accompanied by extremely low superoxide (O2-) 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 [125I]-Ang-(1-7) to bovine aortic endothelial cell membranes with IC50 values of 21±35 and 220±280 nmol/L, respectively. Stimulated NO and O2- release from bovine aortic endothelial cells was directly and simultaneously measured on the cell surface by selective electrochemical nanosensors. Peak concentrations of NO and O2- release by AVE 0991 and Ang-(1-7) (both 10 μmol/L) were not significantly different (NO: 295±20 and 270±25 nmol/L; O2-: 18±2 and 20±4 nmol/L). However, the released amount of bioactive NO was ≈5 times higher for AVE 0991 in comparison to Ang-(1-7). The selective Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7) inhibited the AVE 0991-induced NO and O2- production by ≈50%. A similar inhibition level was observed for the Ang II AT2 receptor antagonist EXP 3174. In contrast, the Ang II AT2 receptor antagonist PD 123,177 inhibited the AVE 0991-stimulated NO production by ≈90% but without any inhibitory effect on O2- production. Both NO and O2- production were inhibited by NO synthase inhibition (≈70%) and by bradykinin B2 receptor blockade (≈80%). 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.
|Original language||English (US)|
|Number of pages||6|
|State||Published - Dec 1 2002|
- Nitric oxide
- Nitric oxide synthase
ASJC Scopus subject areas
- Internal Medicine