Angiotensin-(1-7) Reduces Norepinephrine Release Through a Nitric Oxide Mechanism in Rat Hypothalamus

Abstract

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...

Angiotensin-(1-7) attenuates hypertension and cardiac hypertrophy via modulation of nitric oxide and neurotransmitter levels in the paraventricular nucleus in salt-sensitive hypertensive rats

“…10,41 Previous studies have demonstrated that Ang-(1-7) inhibits NE release via a NO-dependent mechanism in the rat hypothalamus. 42,43 In the current study, markedly increased glutamate and NE levels and a reduced level of GABA in the PVN were observed in HS rats compared to that in NS rats. Moreover, we found that HS rats had a higher level of tyrosine hydroxylase (TH; a marker used to recognize adrenergic neurons) and a lower level of 67 kDa isoform of glutamate decarboxylase (GAD67; a marker used to identify GABAergic neurons) expression within the PVN compared to that in NS rats, implying improved excitatory adrenergic activities and attenuated GABAergic activity in the PVN.…”

Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats

“…In contrast, ANG-(1-7) is also known to mediate sympathoexcitatory effects in RVLM (12) and paraventricular nucleus of the hypothalamus (39). However, recent data have shown that ANG-(1-7) inhibits norepinephrine release in hypothalamus through nitric oxide pathway in different models of hypertension and prevents the ANG II stimulatory effect in this region (13)(14)(15). Even though some acute studies have shown an excitatory effect of ANG-(1-7), it is important to consider that chronic studies clearly show that ANG-(1-7) mediates antihypertensive effects in the brain.…”

The Endothelium-Dependent Vasodilator Effect of the Nonpeptide Ang(1-7) Mimic AVE 0991 Is Abolished in the Aorta of Mas-Knockout Mice

“…Probably not. Many previous studies suggest that, in addition to the interaction with the A-779-sensitive receptor Mas, [7][8][9][10]14 Ang (1-7) is capable of interacting with ACE 4 and AT 1 3,30 and AT 2 -like receptors 31 or, more likely, with Mas-AT 1 and/or Mas-AT 2 oligomers. 14,32 Several studies have shown that Ang(1-7) may play an important hemodynamic role by increasing baroreflex sensitivity, 33 modulating vascular reactivity to angiotensin II 27,28 and bradykinin, 4,19,20,23 and influencing cardiac output.…”