ACE inhibitor potentiation of bradykinin-induced venoconstriction

Abstract

1. Angiotensin-converting enzyme (ACE) inhibitors exert their cardiovascular effects 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 B₂ receptor. We have investigated whether this is a specific effect 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 B₂ receptor.

2. Moexiprilat and ramiprilat (⩽ 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 effect on the constrictor response to AII or the dilator response to acetylcholine.

3. The bradykinin-potentiating effect 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 μM), an angiotensin I metabolite, significantly enhanced the constrictor response to bradykinin.

4. Ramiprilat did not alter the binding of [³H]-bradykinin to a membrane fraction prepared from endothelium-denuded rabbit jugular veins or to cultured fibroblasts, and there was no ACE inhibitor-sensitive, bradykinin-induced cleavage of the B₂ receptor in cultured endothelial cells.

5. These findings demonstrate that ACE inhibitors selectively potentiate the B₂ receptor-mediated vascular effects of bradykinin. Their relative efficacy appears to be independent of their ACE-inhibiting properties and might be related to differences 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 affinity of the B₂ receptor or a prevention of its desensitization, but may involve an increase in the intrinsic activity of unoccupied B₂ receptor molecules.

Full Text

The Full Text of this article is available as a PDF (351.7 KB).