Abstract-Angiotensin (Ang)-(1-7) elicits a facilitatory presynaptic effect on peripheral noradrenergic neurotransmission, and because biological responses to the heptapeptide on occasion are tissue specific, the present investigation was undertaken to study its action on noradrenergic neurotransmission at the central level. In rat hypothalamus labeled with [ 3 H]-norepinephrine, 100 to 600 nmol/L Ang-(1-7) diminished norepinephrine released by 25 mmol/L KCl. This effect was blocked by the selective angiotensin type 2 receptor antagonist PD 123319 (1 mol/L) and by the specific Ang-(1-7) receptor antagonist ]Ang-(1-7) (1 mol/L) but not by losartan (10 nmol/L to 1 mol/L), a selective angiotensin type 1 receptor antagonist. The inhibitory effect on noradrenergic neurotransmission caused by Ang-(1-7) was prevented by 10 mol/L N -nitro-L-arginine methylester, an inhibitor of nitric oxide synthase activity, and was restored by 100 mol/L L-arginine, precursor of nitric oxide synthesis. Methylene blue (10 mol/L), an inhibitor of guanylate cyclase considered as the target of nitric oxide action, as well as Hoe 140 (10 mol/L), a bradykinin B 2 -receptor antagonist, prevented the inhibitory effect of the heptapeptide on neuronal norepinephrine release, whereas no modification was observed in the presence of 0.1 to 10 mol/L indomethacin, a cyclooxygenase inhibitor. Our results indicate that Ang-(1-7) has a tissue-specific neuromodulatory effect on noradrenergic neurotransmission, being inhibitory at the central nervous system by a nitric oxide-dependent mechanism that involves angiotensin type 2 receptors and local bradykinin production. Key Words: angiotensin Ⅲ norepinephrine Ⅲ nitric oxide Ⅲ angiotensin antagonist Ⅲ bradykinin Ⅲ prostaglandins A ngiotensin (Ang)-(1-7) is considered a bioactive end product of the renin-angiotensin system formed from Ang I metabolism through an enzymatic pathway independent of the angiotensin-converting enzyme. 1 It can be formed either from Ang I or Ang II by a prolyl-endopeptidase that cleaves the Pro-Phe bond. 1,2 Ferrario and coworkers 2 demonstrated the presence of Ang-(1-7) in several regions of the rat brain such as the hypothalamus, amygdala, and medulla oblongata but not in the cerebral cortex and cerebellum. In addition, type 1 (AT 1 ) and type 2 (AT 2 ) Ang receptors were described in several regions and nucleus of the central nervous system, including the hypothalamus. 3,4 Although Ang-(1-7) is not an agonist in terms of activating vasoconstriction, 5 stimulating thirst, 6 or promoting aldosterone secretion, 5 the heptapeptide causes neuronal excitation in the paraventricular nucleus of hypothalamus and dorsal vagal complex of the medulla oblongata, 7 facilitates the noradrenergic neurotransmission, 8 and stimulates prostaglandin 9 -11 and vasopressin release 12 with potency comparable to that of Ang II. Conversely, some of the effects of Ang-(1-7) are opposite to those elicited by Ang II, that is, it displays an antiproliferative action on vascular smooth muscle cells, 13 produ...
