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(Hypertension. 2004;44:783.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Angiotensin-(1–7) Inhibitory Mechanism of Norepinephrine Release in Hypertensive Rats

From the Departamento de Química Biológica, Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.

Correspondence to Dr Mariela M. Gironacci, Departamento de Química Biológica e Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina. E-mail mariela{at}qb.ffyb.uba.ar

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.

Key Words: angiotensin • norepinephrine • receptors, angiotensin II • kinins • nitric oxide • angiotensin antagonist • bradykinin

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