Relaxation of Isolated Coronary Arteries by Angiotensin-Converting Enzyme Inhibitors: Role of Endothelium-Derived Kinins

Abstract

In the presence of indomethacin (10 µM) and without previous exposure to bradykinin, two angiotensin-converting enzyme (ACE) inhibitors, moexiprilat and ramiprilat (0.1 µM), elicited distinct relaxation responses from preconstricted endothelium-intact but not from denuded bovine coronary artery rings, and enhanced the relaxation response to bradykinin (3 nM). All of these responses were strongly reduced by the selective B2-kinin receptor antagonist Hoe 140 (0.1 µM). Bradykinin (30 nM), moexiprilat or ramiprilat (0.3 µM) also significantly increased the cyclic GMP content of these coronary segments, an effect which was abolished by the nitric oxide (NO) synthase inhibitor N^G-nitro-L-arginine (L-NNA; 30 µM) or by removal of the endothelium. L-NNA also strongly reduced the relaxation response to moexiprilat but only partially inhibited that to bradykinin, demonstrating that the ACE inhibitor-induced relaxation was predominantly mediated by endothelial NO release, whereas bradykinin acted in part through another endothelium-dependent mechanism. These findings suggest that ACE inhibitors induce endothelium-dependent relaxation presumably by facilitating the accumulation of endothelium-derived vasoactive kinins in or at the vessel wall. This local mechanism may significantly contribute to the dilator action of these compounds in vivo.

Display of the characteristics of endothelium‐derived hyperpolarizing factor by a cytochrome P450‐derived arachidonic acid metabolite in the coronary microcirculation

“…This finding suggests that the EDHF-induced dilatation is not simply a response observed following inhibition of the synthesis of the other dilatory autacoids, but represents a substantial constitutive component of the dilator response to bradykinin in the coronary microcirculation under physiological conditions. Moreover, therapeutics such as angiotensin-converting enzyme inhibitors, which have been shown to restore impaired endothelium-dependent vasodilatations, enhance both the NO-mediated and the NO/PGI2-independent dilator response to bradykinin in isolated coronary arteries (Mombouli et al, 1992;Hecker et al, 1993), indicating that part of the beneficial cardiovascular action of these drugs may be related to an enhanced synthesis and release of EDHF.…”

Potentiation by ACE inhibitors of the dilator response to bradykinin in the coronary microcirculation: interaction at the receptor level

“…Macmillan Press Ltd, 1994 release of both PGI2 and NO from cultured endothelial cells, an effect which is mediated by a B2-receptor-dependent increase in intracellular Ca2+ (Wiemer et al, 1991;Busse & Lamontagne, 1991). In the absence of exogenous bradykinin, ACE inhibitors can also elicit endothelium-dependent, largely NO-mediated relaxations of bovine and porcine coronary arteries which are antagonized by the specific B2-receptor antagonist, Hoe 140 (Hecker et al, 1993a). Thus, in certain vascular beds there may be a continuous synthesis of vasoactive kinins from an endogenous source, the release of which can stimulate endothelial autacoid formation in an auto-or paracrine manner when their local concentration exceeds a critical threshold level.…”

“…However, besides promoting the accumulation of endothelium-derived kinins, ACE inhibitors may also amplify the action of bradykinin at the receptor level (Auch-Schwelk et al, 1993;Hecker et al, 1993a). To address this possibility further, we have (i) investigated the effects of an active and a very weakly active, structurally related ACE inhibitor on the vasodilator response to bradykinin in the isolated salineperfused rabbit heart, (ii) compared the magnitude and time course of these responses with those elicited by the putatively ACE-resistant B2-receptor agonist, D-Arg[Hyp3J-bradykinin (Rhaleb et al, 1990), and (iii) examined the effects of these ACE inhibitors on the constrictor action of bradykinin in ring segments of the rabbit jugular vein.…”

Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema

“…1,3 Bradykinin relaxes arterial blood vessels through activation of eNOS and has therefore no such effect in endothelium-denuded arteries or arteries pretreated with inhibitors of eNOS, such as L-NAME. 29 Nitric oxide-dependent vasodilator responses are mediated by activation of soluble guanylyl cyclase, generation of cGMP, and activation of cGMP-dependent protein kinase. 30 The latter kinase phosphorylates a variety of cellular proteins, including VASP, and Ser239 VASP phosphorylation has been shown to be cGMP dependent and specific.…”