Angiotensin-(1-7) Dilates Canine Coronary Arteries Through Kinins and Nitric Oxide

Abstract

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.

Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

“…The present study adds to growing evidence that suggests the involvement of Ang-(1-7) receptors in cardiac regulation both in normal (Gironacci et al, 1994;Porsti et al, 1994;Brosnihan et al, 1996) or pathological conditions (Ferreira et al, 2001;Loot et al, 2002;Zisman et al, 2003). In addition, our results suggest that losartan might interfere with Ang-(1-7) receptors in the regulation of cardiac chronotropism, which probably accounts for the orthostatic hypotension observed in losartan, but not in candesartan, treated rats.…”

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension

“…Indeed, microinjection of bradykinin into the NTS have been shown to produce a dose-dependent decrease in mean arterial pressure, a hypotension mainly determined by a decrease in the sympathetic system activity. 48 Our present results of a blockade of the vasodepressor response to footshocks with central administration of the kinin B 2 antagonist or inhibition of NO formation suggest that during blockade of the AT 1 receptor, activation of AT 2 receptors may lead to an increase in either brain kinins concentration or the effect of kinins, 43 which in turn may release NO. These substances, at different central sites, may shift toward a sympatho-inhibitory effect manifested as a hypotensor response to footshocks.…”

“…14 Our data of blockade of the vasodepressor response to footshocks with the kinin B 2 receptor antagonist or with nitric oxide synthase inhibition suggests that during blockade of the angiotensin AT 1 receptor, activation of angiotensin AT 2 or AT n receptors may lead to an increase in either tissue kinins concentration or the effect of kinins, and the subsequent release of nitric oxide. 43 In regard to the central nervous system, increasing evidence has suggested that there is a close interaction between NO and angiotensin II. 44 Although the present study does not provide direct evidence for the site of action of the NO-angiotensin II interaction, it could be proposed that it is mediated within brain structures known to alter sympathetic outflow such as the NTS, the DMV and the RVLM, all of which play important roles in the regulation of sympathetic activity.…”

The role of bradykinin, AT2 and angiotensin 1–7 receptors in the EDRF‐dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat

“…Unlike other vascular beds, where A 779, a putative Ang 1-7 antagonist (Santos et al, 1994), inhibits the vasodilator effect of Ang 1-7 (Bayorh et al, 2002;Ren et al, 2002), our results demonstrate that the vasodilator effect of Ang 1-7 on the MVB could involve other receptors, given that A 779 does not inhibit Ang 1-7 vasodilation. BK appears to modulate Ang 1-7-induced vasodilation, since several reports have shown that the vasodilator effect of BK is enhanced by Ang 1-7 and vice versa (Brosnihan et al, 1996;Gorelik et al, 1998;Almeida et al, 2000;Fernandes et al, 2001;Tom et al, 2001). Also, the involvement of BK in the vasodilator effect of Ang 1-7 is suggested by Brosnihan et al (1996), who demonstrated that the vasodilator effect of Ang 1-7 was inhibited by HOE 140.…”

“…Ang 1-7, a potent vasodilator compound (Meng & Busija, 1993;Osei et al, 1993;Po¨rsti et al, 1994;Brosnihan et al, 1996;Ren et al, 2002), could be involved in the mechanism of the action of Ang II in the rat MVB. Ang II could be transformed into Ang 1-7 by carboxypeptidase P, or might also stimulate the Ang 1-7 receptor (Ferrario et al, 1990).…”