Angiotensin-(1-7) reduces norepinephrine release through a nitric oxide mechanism in rat hypothalamus

Angiotensin (Ang)-(1-7) elicits a facilitatory presynaptic effect on periph eral noradrenergic neurotransmission, and because biological responses to t he heptapeptide on occasion are tissue specific, the present investigation was undertaken to study its action on noradrenergic neurotransmission at th e central level, In rat hypothalamus labeled with [H-3]-norepinephrine, 100 to 600 nmol/L Ang-(1-7) diminished norepinephrine released by 25 mmol/L KC l. This effect was blocked by the selective angiotensin type 2 receptor ant agonist PD 123319 (1 mu mol/L) and by the specific Ang-(1-7) receptor antag onist [D-Ala(7)]Ang-(1-7) (1 mu mol/L) but not by losartan (10 nmol/L to 1 mu mol/L), a selective angiotensin type 1 receptor antagonist. The inhibito ry effect on noradrenergic neurotransmission caused by Ang-(1-7) was preven ted by 10 mu mol/L N-omega-nitro-L-arginine methylester, an inhibitor of ni tric oxide synthase activity, and was restored by 100 mu mol/L L-arginine, precursor of nitric oxide synthesis. Methylene blue (10 mu mol/L), an inhib itor of guanylate cyclase considered as the target of nitric oxide action, as well as Hoe 140 (10 mu mol/L), a bradykinin B-2-receptor antagonist, pre vented the inhibitory effect of the heptapeptide on neuronal norepinephrine release, whereas no modification was observed in the presence of 0.1 to 10 mu mol/L indomethacin, a cyclooxygenase inhibitor. Our results indicate th at Ang-(1-7) has a tissue-specific neuromodulatory effect on noradrenergic neurotransmission, being inhibitory at the central nervous system by a nitr ic oxide-dependent mechanism that involves angiotensin type 2 receptors and local bradykinin production.