Potentiation of the vascular response to kinins by inhibition of myocardial kininases

Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B-2 receptor-mediated vasodilation even after desensitization of this re ceptor. Because this activity cannot be easily explained only by an inhibit ion of kinin degradation, direct interactions of ACE inhibitors with the B- 2 receptor or its signal transduction have been hypothesized. To clarify th e significance of degradation-independent potentiation, we studied the vaso dilatory effects of BK and 2 degradation-resistant B-2 receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) co ntribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B- 2 agonist was assessed in the presence or absence of the ACE inhibitor rami prilat, the APP inhibitor mercaptoethanol, or both, Ramiprilat or mercaptoe thanol induced leftward shifts in the BK dose-response curve (EC50=3.4 nmol /L) by a actor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC50 of BK to 0.18 nmol/L (ie, by a factor of 19) but poten tiated the activity of B6014 (EC50=1.9 nmol/L) only weakly without altering that of FR190997 (EC50=0.34 nmol/L). Desensitization of B-2 receptors was induced by the administration of BK (0.2 mu mol/L) or FR190997 (0.1 mu mol/ L) for 30 minutes; the vascular reactivity to ramiprilat or increasing dose s of BK was tested thereafter. After desensitization with BK, but not FR190 997, an additional application of ramiprilat provoked a B-2 receptor-mediat ed vasodilation. High BK concentrations were still effective at the desensi tized receptor. The process of desensitization was not altered by ramiprila t, These results show that in this model, all potentiating actions of ACE i nhibitors on kinin-induced vasodilation are exclusively related to the redu ction in BK breakdown and are equivalently provoked by APP inhibition. The desensitization of B-2 receptors is overcome by increasing BK concentration s, either directly or through the inhibition of ACE. These observations do not suggest any direct interactions of ACE inhibitors with the B-2 receptor or its signal transduction but point to a very high activity of BK degrada tion in the vicinity of the B-2 receptor in combination with a stimulation- dependent reduction in receptor affinity.