Abstract-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 (AT 2 ) 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 [ 3 H]NE. [ 3 H]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 ϩ -induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist ]Ang-(1-7), the AT 2 receptor antagonist PD 123319, and the BK B 2 receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K ϩ -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 AT 2 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. ] has been shown to be the most pleiotropic bioactive component of the renin-angiotensin system because it exerts effects that may be identical to, different from, or opposite from those displayed by angiotensin II (Ang II). 1 For instance, it lacks the vasoconstrictor aldosterone secretagogue or dipsogenic effects of Ang II. 1,2 However, it mimics Ang II stimulation of vasopressin and prostaglandin release 1 as well as peripheral norepinephrine (NE) outflow. 3 In contrast, Ang-(1-7) causes natriuresis, diuresis, and vasodilatation and inhibits angiogenesis and cellular growth, 1,2 suggesting that in many cases, this peptide may act as an endogenous antagonist of Ang II. In fact, Ang-(1-7) has been suggested as having an antihypertensive effect as well as counterbalancing the pressor and proliferative actions of Ang II because some of its effects that oppose those of Ang II are enhanced in rat models of hypertension. 1,4 It has been demonstrated that the Mas proto-oncogene, originally considered to be an "orphan" G-protein-coupled receptor involved in phospholipase C activation, 5 binds Ang-(1-7) and is involved in the biological actions of this heptapeptide. 6 Genetic deletion of the Mas receptor abolishes not only binding of Ang-(1-7) to mouse kidneys but also Ang-(1-7)-induced relaxation and antidiuretic responses, suggesting that ...

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