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

Abstract

Abstract-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 (AT 2 ) 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 [ 3 H]NE. [ 3 H]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 ϩ -induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist ]Ang-(1-7), the AT 2 receptor antagonist PD 123319, and the BK B 2 receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K ϩ -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 AT 2 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. ] has been shown to be the most pleiotropic bioactive component of the renin-angiotensin system because it exerts effects that may be identical to, different from, or opposite from those displayed by angiotensin II (Ang II). 1 For instance, it lacks the vasoconstrictor aldosterone secretagogue or dipsogenic effects of Ang II. 1,2 However, it mimics Ang II stimulation of vasopressin and prostaglandin release 1 as well as peripheral norepinephrine (NE) outflow. 3 In contrast, Ang-(1-7) causes natriuresis, diuresis, and vasodilatation and inhibits angiogenesis and cellular growth, 1,2 suggesting that in many cases, this peptide may act as an endogenous antagonist of Ang II. In fact, Ang-(1-7) has been suggested as having an antihypertensive effect as well as counterbalancing the pressor and proliferative actions of Ang II because some of its effects that oppose those of Ang II are enhanced in rat models of hypertension. 1,4 It has been demonstrated that the Mas proto-oncogene, originally considered to be an "orphan" G-protein-coupled receptor involved in phospholipase C activation, 5 binds Ang-(1-7) and is involved in the biological actions of this heptapeptide. 6 Genetic deletion of the Mas receptor abolishes not only binding of Ang-(1-7) to mouse kidneys but also Ang-(1-7)-induced relaxation and antidiuretic responses, suggesting that ...

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

“…23 Additional evidence suggests that Ang-(1-7) reduces the release of norepinephrine acting through a BK/ nitric oxide-mediated mechanism that stimulates cGMP/ protein kinase G signaling. 24 Other experiments also point to an interrelationship between Ang-(1-7) and the prostaglandin-BK-nitric oxide system. In the spontaneously hypertensive rat (SHR), the vasodilator effects of Ang-(1-7) are blocked in the presence of the cyclooxygenase 1 inhibitor, indomethacin, 25 confirming previous findings in which the vasorelaxing response of canine coronary artery ring induced by Ang-(1-7) was abolished by the BK antagonist icatibant, 26 whereas the peptide also inhibited the degradation of 125 I-[Tyr 0 ]-BK and the appearance of BK-(1-7) and BK-(1-5) metabolites in the effluent from the preparation.…”

Angiotensin-(1–7) and Bradykinin in Norepinephrine Release in the Central Nervous System of Hypertension

“…[3][4][5] In a study we presented earlier, the change in NE release induced by BK was investigated in the hypothalamus of normotensive and hypertensive rats. 6,7 In an in vitro study using rat brain slices, we showed that BK increased the stimulation-evoked NE release in a dose-dependent manner.…”

“…In addition, the inhibitory effect of Ang-(1-7) was also blocked in the presence of an inhibitor of nitric oxide synthesis, suggesting that endogenous BK is mediating nitric oxide release, and in this way Ang-(1-7) diminishes NE release. 4 Therefore, since central endogenous levels of BK are very low, 1 a synergistic effect between BK and Ang-(1-7) on NE release is not expected, as Dr Tsuda suggested. On the other hand, synergy means "working together", 5 so we would not expect to see a synergistic effect between Ang-(1-7) and BK on NE release when they have an antagonistic effect on that mechanism.…”

“…On the other hand, synergy means "working together", 5 so we would not expect to see a synergistic effect between Ang-(1-7) and BK on NE release when they have an antagonistic effect on that mechanism. 3,4 Furthermore, adding exogenous peptides such as BK has limitations: Not only do the concentrations added fail to mimic endogenous levels, but also these exogenous concentrations of BK may not mimic the site of release and action of endogenous kinins because these peptides act mainly as autocrine (at the site of release) and paracrine autacoids (near the site of release) and not as endocrine hormones. 6 Mariela M. Gironacci …”

Angiotensin-(1-7) and Bradykinin in Baroreceptor Reflex Sensitivity in Hypertension

“…2,3 It was demonstrated that Ang-(1-7) and bradykinin can interact to modulate baroreflex control of the heart rate, suggesting that the centrally modulatory effect of Ang-(1-7) on the baroreflex might be mediated, at least in part, by the release of kinins. 2 Gironacci et al 4 demonstrated that Ang-(1-7) decreased K + -induced norepinephrine release in the hypothalamus of spontaneously hypertensive rats by the nitric oxide and bradykinin B2 receptor-dependent mechanisms. It can be speculated that the interactions between Ang-(1-7) and bradykinin might have a crucial role in the central modulation of BRS.…”