Release of nitric oxide by angiotensin‐(1–7) from porcine coronary endothelium: implications for a novel angiotensin receptor

Abstract

The angiotensin I (AI) metabolite, A(1-7), elicited a concentration-dependent dilator response (ED50 > or = 2 microM) in porcine coronary artery rings which was markedly attenuated by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine, and abolished after removal of the endothelium. This effect of the heptapeptide was not mimicked by AII, AIII or A(3-8) at comparable concentrations. The A(1-7)-induced relaxation was not affected by AT1 or AT2 receptor blockade or cyclo-oxygenase inhibition, but was attenuated by the B2 receptor antagonist, Hoe 140, and augmented by the angiotensin-converting enzyme (ACE) inhibitor, quinaprilat. These findings suggest that the relaxation to A(1-7) was mediated by the release of NO from the coronary endothelium through activation of an, as yet unidentified, AT receptor, the occupation of which also seems to stimulate the release of vasoactive kinins. Since A(1-7) accumulates during ACE inhibition, this mechanism may contribute to the coronary dilator effect of ACE inhibitors in vivo.

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.…”

“…Taken together, the results of the present and previous studies (Ferreira et al, 2001;Collister & Hendel, 2003) suggest that losartan might be interfering in a chronotropic regulatory action mediated by Ang-(1-7) receptors. In this regard, there is pharmacological evidence for the presence of a selective Ang-(1-7) receptor in the heart (Ferreira et al, 2001) and coronary arteries (Porsti et al, 1994). In addition, immunoreactivity for Ang-(1-7) was recently detected in cardiac myocites (Averill et al, 2003).…”

Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis

“…Arterial splanchnic vasodilation was consistently detected in human cirrhosis [8,19] . A large number of studies have demonstrated the vasodilatory effect of Ang-(1-7) [20][21][22][23] . Possible mechanisms for this effect include bradykinin potentiation [21,22] , enhanced prostacyclin (PGI2) release from vascular smooth muscle cells [23] and direct stimulation of nitric oxide (NO) synthesis [20,22] .…”

“…A large number of studies have demonstrated the vasodilatory effect of Ang-(1-7) [20][21][22][23] . Possible mechanisms for this effect include bradykinin potentiation [21,22] , enhanced prostacyclin (PGI2) release from vascular smooth muscle cells [23] and direct stimulation of nitric oxide (NO) synthesis [20,22] . NO, PGI2, carbon monoxide, endocannabinoids and other vasodilators have been associated with arterial splanchnic vasodilation [24] .…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…It was later shown that Ang-(1-7) produced endothelium-dependent dilation of the coronary arteries of pigs and dogs, which was mediated by NO and bradykinin (Porsti et al 1994;Brosnihan et al 1996). This response was independent of AT 1 or AT 2 receptors, or prostaglandins; however, ACE inhibition magnified the vasodilatory response of Ang-(1-7).…”