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

Abstract

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 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.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Picomolar concentrations of Ang(1-7) were reported to cause a significant vasodilator effect in isolated rat hearts (Souza et al, 2013). Acute stimulation with Ang(1-7) in cardiomyocytes has no evident effect on calcium transients but stimulates release of NO (Dias-Peixoto et al, 2008;Costa et al, 2010;Gomes et al, 2010). However, an increased uptake and SERCA2 expression in transgenic rats overexpressing Ang(1-7) was reported by Gomes et al (2012).…”

Angiotensin-(1–7) attenuates hypertension in exercise-trained renal hypertensive rats

“…A number of studies have been reported about the antihypertensive effect of ANG-(1-7) in different hypertensive models using high fructose diet-fed rats (20), SHR (10,40), SHR treated with N-nitro-L-arginine methyl ester (2), and 2K1C rats (5). In contrast, ANG-(1-7) does not prevent ANG II -induced hypertension (9,21) and neither chronic infusion of ANG-(1-7) nor overproduction of ANG-(1-7) in transgenic rats modifies the course of 2K1C hypertension (5).…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…In cardiomyocytes, acute Mas stimulation with Ang-(1-7) has no demonstrable effect on Ca 2+ transients but promotes NO release by activating endothelial nitric oxide synthase (eNOS) and neuronal NOS (Dias-Peixoto et al, 2008;Costa et al, 2010;Gomes et al, 2010). On the other hand, chronic Mas stimulation or genetic deletion of Mas (Mas-KO; Table 2) produces significant effects on Ca 2+ handling proteins (Santos et al, 2006;Gomes et al, 2012).…”