• Am. J. Physiol. Heart Circ. Physiol. · Oct 2010

    Angiotensin-(1-7) upregulates cardiac nitric oxide synthase in spontaneously hypertensive rats.

    • María A Costa, María A Lopez Verrilli, Karina A Gomez, Pablo Nakagawa, Clara Peña, Cristina Arranz, and Mariela M Gironacci.
    • Cátedra de Fisiología, Instituto de Química y Metabolismo del Fármaco, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Buenos Aires, Argentina.
    • Am. J. Physiol. Heart Circ. Physiol. 2010 Oct 1; 299 (4): H1205-11.

    AbstractIt 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 endothelial (eNOS), neuronal (nNOS), and inducible NOS (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 using the NADPH diaphorase histochemical method and by the conversion of L-[(14)C]arginine to citrulline, and NOS phosphorylation and expression were determined using Western blotting. In SHR, ANG-(1-7) infusion diminished mean arterial pressure from 180 ± 9 to 146 ± 9 mmHg (P < 0.05), and this effect was prevented by nitro-l-arginine methyl ester (l-NAME), a NOS inhibitor. In addition, NOS activity and eNOS phosphorylation were increased by ANG-(1-7) infusion. Ventricular eNOS and nNOS expression were increased 67.4 ± 6.4 and 51 ± 10%, respectively, by ANG-(1-7), whereas 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 AT(2) and a bradykinin B(2) receptor antagonist, but not by the Mas receptor antagonist. Our results show that in rats in a hypertensive state, ANG-(1-7) infusion upregulates cardiac NOS expression and activity through an AT(2)- and bradykinin-dependent mechanism. In this way ANG-(1-7) may elicit its cardioprotective action and contribute to some of the counterregulatory AT(2) receptor effects that oppose the AT(1) receptor-mediated effects.

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