Angiotensin-(1-7) inhibitory mechanism of norepinephrine release in hypertensive rats

Release of norepinephrine (NE) by the hypothalamic nuclei may contribute to regulation of sympathetic nervous system (SNS) activity. Angiotensin-(1-7) [Ang-(1-7)] has an antihypertensive effect and may decrease SNS activity. We tested the hypothesis that Ang-(1-7) inhibits the release of NE in hypothalami, via the Ang-(1-7) and angiotensin II type 2 (AT2) receptors, acting through a bradykinin (BK)/NO-dependent mechanism. Hypothalami from normotensive controls and spontaneously hypertensive rats (SHR) were isolated and endogenous NE stores labeled by incubating the tissues with [3H]NE. [3H]NE release from the hypothalami was stimulated by KCl in the presence or absence of Ang-(1-7) alone or combined with various antagonists and inhibitors. Ang-(1-7) significantly attenuated K+-induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist [D-Ala7]Ang-(1-7), the AT2 receptor antagonist PD 123319, and the BK B2) receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K+-stimulated NE release in SHR. The inhibitory effect of Ang-(1-7) disappeared in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and was restored by the precursor of NO, l-arginine. The diminished NE release caused by Ang-(1-7) was blocked by a soluble guanylyl cyclase inhibitor as well as by a cGMP-dependent protein kinase (PKG). We concluded that Ang-(1-7) decreases NE release from the hypothalamus via the Ang-(1-7) or AT2 receptors, acting through a BK/NO-mediated mechanism that stimulates cGMP/PKG signaling. In this way, Ang-(1-7) may decrease SNS activity and exert an antihypertensive effect.