1 To examine the possibility that angiotensin-converting enzyme (ACE) inhibitors modulate the action of bradykinin at the receptor level, their effect on the dilator response to bradykinin was studied in the isolated saline-perfused heart of the rabbit. 2 Continuous infusion of bradykinin (10 nM) elicited a transient decrease in coronary perfusion pressure (CPP) and increased prostacyclin (PGI(2)) release which returned to baseline values within 30 min. 3 Subsequent co-infusion of ramiprilat (greater than or equal to 10 nM) or moexiprilat, but not of the less potent ACE inhibitor n-octyl-ramipril (RA-octyl), caused another fall in CPP and an increase in PGI(2) release, the magnitude and time course of which were almost identical to the first response to bradykinin. No change in CPP or PGI(2) release was observed when the ACE inhibitors were administered in the absence of exogenous bradykinin. 4 Infusion of D-Arg[Hyp(3)]-bradykinin (10 nM), a specific B-2-receptor agonist which was significantly more resistant to degradation by ACE than bradykinin, produced virtually identical changes in CPP and PGI(2) release when compared to bradykinin. Subsequent co-infusion of ramiprilat was similarly effective in restoring the fall in CPP and increase in PGI(2) release elicited by D-Arg[Hyp(3)]-bradykinin as in the presence of bradykinin. 5 In concentrations which should block the degradation of bradykinin by ACE in the coronary vascular bed, two ACE substrates, hippuryl-L-histidyl-L-leucine (0.2 mM) and angiotensin I (0.3 mu M), were unable to elicit a significant change in CPP or PGI(2) release while ramiprilat and another ACE inhibitor, quinaprilat, were still active in the presence of these substrates. 6 To reveal the potential B-2-receptor action of ramiprilat, its effect on the constrictor response to bradykinin was studied in the rabbit isolated jugular vein. Ramiprilat (0.1 mu M), but not RA-octyl (1 mu M), potentiated the endothelium-independent, B-2-receptor-mediated constrictor response to bradykinin, but not that to the thromboxane-mimetic U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxymethano-prostaglandin F-2 alpha) Moreover, ramiprilat but not RA-octyl caused a concentration-dependent, B-2-receptor antagonist-sensitive increase in tone when administered alone. 7 These findings suggest that an interaction of ACE inhibitors with the B-2-receptor or its signal transduction pathway rather than an accumulation of bradykinin within the vascular wall is responsible for the restoration of the endothelial response to bradykinin (dilatation, PGI(2) release) in the coronary vascular bed of the rabbit.
