CONICET | Buscador de Institutos y Recursos Humanos

It has been shown that angiotensin (Ang) (1-7) activates nitric oxide synthase (NOS) in isolated ventricular myocytes from normotensive rats. Since many Ang-(1-7) actions are enhanced in situations of increased Ang II activity, as in hypertension, in this study we investigated the in vivo effect of Ang-(1-7) on NOS activity and expression of eNOS, nNOS and iNOS in ventricles from spontaneously hypertensive rats (SHR). Rats were subjected to a 60 min Ang-(1-7)-infusion (0.35 nmol/min), controls received saline. NOS activity was measured by the NADPH diaphorase histochemical method and by the conversion of [14C]L-arginine to citrulline, and NOS phosphorylation and expression by Western-blot. In SHR Ang-(1-7) infusion diminished mean arterial pressure from 180±9 mmHg to 146±9 mmHg (p<0.05) and this effect was prevented by L-NAME, a NOS inhibitor. In addition, NOS activity and eNOS phosphorylation were increased by Ang-(1-7) infusion. Ventricular eNOS and nNOS expression increased by 67.4+6.4% and 51+10%, respectively, by Ang-(1-7) while iNOS was not changed. In another set of experiments we evaluated the mechanism by which Ang-(1-7) modifies NOS activity. Isolated ventricle slices preincubated with Ang-(1-7) showed an increase in NOS activity and eNOS phosphorylation, which was blocked by an AT2- and a bradykinin B2-receptor antagonist, but not by the Mas receptor antagonist. Our results show that in a hypertensive state Ang-(1-7) infusion upregulates cardiac NOS expression and activity through an AT2- and a bradykinin dependent mechanism. In this way Ang-(1-7) may elicit its cardioprotective action and contribute to some of the counter regulatory AT2 receptor effects that oppose the AT1 receptor-mediated effects.