ACE inhibitor potentiation of bradykinin‐induced venoconstriction

Abstract

1 Angiotensin-converting enzyme (ACE) inhibitors exert their cardiovascular e ects not only by preventing the formation of angiotensin II (AII), but also by promoting the accumulation of bradykinin in or at the vessel wall. In addition, certain ACE inhibitors have been shown to augment the vasodilator response to bradykinin, presumably by an interaction at the level of the B 2 receptor. We have investigated whether this is a speci®c e ect of the ACE inhibitor class of compounds in isolated endothelium-denuded segments of the rabbit jugular vein where bradykinin elicits a constrictor response which is exclusively mediated by activation of the B 2 receptor. 2 Moexiprilat and ramiprilat (4 3 nM) enhanced the constrictor response to bradykinin three to four fold. Captopril and enalaprilat were less active by approximately one and quinaprilat by two orders of magnitude. Moexiprilat and ramiprilat, on the other hand, had no e ect on the constrictor response to AII or the dilator response to acetylcholine. 3 The bradykinin-potentiating e ect of the ACE inhibitors was not mimicked by inhibitors of amino-, carboxy-, metallo-or serine peptidases or the synthetic ACE substrate, hippuryl-L-histidyl-L-leucine, at a concentration which almost abolished the residual ACE activity in the vessel wall. In contrast, angiotensin-(1 ± 7) (10 mM), an angiotensin I metabolite, signi®cantly enhanced the constrictor response to bradykinin. 4 Ramiprilat did not alter the binding of [ 3 H]-bradykinin to a membrane fraction prepared from endothelium-denuded rabbit jugular veins or to cultured ®broblasts, and there was no ACE inhibitorsensitive, bradykinin-induced cleavage of the B 2 receptor in cultured endothelial cells. 5 These ®ndings demonstrate that ACE inhibitors selectively potentiate the B 2 receptor-mediated vascular e ects of bradykinin. Their relative e cacy appears to be independent of their ACE-inhibiting properties and might be related to di erences in molecule structure. Moreover, the potentiation of the biological activity of bradykinin by this class of compounds does not seem to be mediated by a shift in a nity of the B 2 receptor or a prevention of its desensitization, but may involve an increase in the intrinsic activity of unoccupied B 2 receptor molecules.

Potentiation of the Vascular Response to Kinins by Inhibition of Myocardial Kininases

“…This interpretation is in agreement with binding studies in which it was also found that there were no alterations in B 2 receptor affinity in the presence of ACE inhibitors. 15,18 In only 1 model of transfected Chinese hamster ovary cells expressing the human B 2 receptor and ACE genes was an increase in the density and affinity of BK binding reported in the presence of enalaprilat. 14 This effect was dependent on the presence of ACE, and it occurred only when enalaprilat was applied in concentrations substantially higher than those needed for the inhibition of the enzymatic activity of ACE, 14 a condition that was not investigated in the present study.…”

“…In the rat heart, the influence of kininase inhibitors on local kinin concentrations has been established in tracer transit studies that demonstrated a marked increase in kinin concentrations during ACE inhibition specifically in an extravascular distribution compartment. 6 Additional observations have been made suggesting that some of the kinin potentiation properties of ACE inhibitors might be related to mechanisms independent of the inhibition of kinin degradation; for example, (1) ACE inhibitors act as kinin mimetics under conditions in which kinin breakdown should be negligible, 10 (2) ACE inhibitors can enhance the effects of degradation-resistant BK analogs, [11][12][13][14] (3) ACE inhibitors show structure-related differences in their kinin potentiation activities, 15 and (4) ACE inhibitors can provoke a kinin-mediated response even when B 2 receptors have been desensitized through kinin pretreatment. 11,13 The last phenomenon is addressed further here as "receptor resensitization."…”

“…In addition to inhibition of BK breakdown, ACE inhibitors could act directly on B 2 receptors or their signal transduction by increasing receptor affinity, preventing receptor internalization, or enhancing second-messenger activation. 14,15 However, none of these mechanisms have ever been demonstrated in a physiological model that can reveal the classic consequences of kinin potentiation, namely a leftward shift in the BK dose-response curve.…”

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

“…110 For this reason ACEis have diverse effects independent of their BP-lowering effect (Figure 2). Indeed, different ACEis like moexiprilate, ramipirilate, captopril, enalpril and quinaprilate amplified the effects of bradykinin in vessels that lacked measurable ACE activity 154 and also enhanced the effect of an ACE-resistant B 2 -kinin receptor agonist. These findings demonstrate that ACEis selectively potentiate the B 2 -receptor-mediated vascular effects of bradykinin independently of their ACE-inhibiting properties, and this might be related to differences in molecular structure.…”

“…These findings demonstrate that ACEis selectively potentiate the B 2 -receptor-mediated vascular effects of bradykinin independently of their ACE-inhibiting properties, and this might be related to differences in molecular structure. 154,155 ACEis also induce cross-talk between the transmembrane protein ACE and the B 2 -kinin receptor, probably by formation of a heterodimer. This protects high-affinity receptors, blocks receptor desensitization and decreases internalization, thereby potentiating BK beyond blocking its hydrolysis.…”