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.
Gironacci
Mariela M
MM
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. mariela@qb.ffyb.uba.ar
Valera
María S
MS
Yujnovsky
Irene
I
Peña
Clara
C
D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology*; D007031:Hypothalamus / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology
D000959:Antihypertensive Agents; D010446:Peptide Fragments; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide; D000803:Angiotensin I; D017869:Cyclic GMP-Dependent Protein Kinases; C118790:angiotensin I (1-7); D009638:Norepinephrine