ramipril and hippuryl-histidyl-leucine

We have recently demonstrated that the angiotensin I-converting enzyme (ACE) inhibitor ramiprilat augments the endothelium-dependent dilator response to bradykinin in the isolated perfused rat heart by an interaction at the B2 receptor level. We have now investigated whether this is an effect of the ACE inhibitor class of compounds by studying the bradykinin-induced vasoconstriction in isolated segments of the rabbit jugular vein. Among five different ACE inhibitors, moexiprilat and ramiprilat proved to be the most effective in potentiating the constrictor response to bradykinin. This effect was not mimicked by other protease inhibitors or the synthetic ACE substrate hippuryl-L-histidyl-L-leucine. The ACE inhibitors, on the other hand, failed to affect the constrictor or dilator responses elicited by other receptor-dependent agonists in this vascular model. These findings demonstrate that ACE inhibitors selectively potentiate the B2 receptor-mediated constrictor response to bradykinin in the rabbit jugular vein, possibly by increasing the affinity of the B2 receptor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Drug Synergism; In Vitro Techniques; Isoquinolines; Jugular Veins; Oligopeptides; Peptidyl-Dipeptidase A; Protease Inhibitors; Rabbits; Ramipril; Rats; Receptor, Bradykinin B2; Receptors, Bradykinin; Tetrahydroisoquinolines; Vasoconstriction

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 (PGI2) release which returned to baseline values within 30 min. 3. Subsequent co-infusion of ramiprilat (> or = 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 PGI2 release, the magnitude and time course of which were almost identical to the first response to bradykinin. No change in CPP or PGI2 release was observed when the ACE inhibitors were administered in the absence of exogenous bradykinin. 4. Infusion of D-Arg[Hyp3]-bradykinin (10 nM), a specific B2-receptor agonist which was significantly more resistant to degradation by ACE than bradykinin, produced virtually identical changes in CPP and PGI2 release when compared to bradykinin. Subsequent co-infusion of ramiprilat was similarly effective in restoring the fall in CPP and increase in PGI2 release elicited by D-Arg[Hyp3]-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 microM), were unable to elicit a significant change in CPP or PGI2 release while ramiprilat and another ACE inhibitor, quinaprilat, were still active in the presence of these substrates. 6. To reveal the potential B2-receptor action of ramiprilat, its effect on the constrictor response to bradykinin was studied in the rabbit isolated jugular vein. Ramiprilat (0.1 MicroM), but not RA-octyl (1 MicroM),potentiated the endothelium-independent, B2-receptor-mediated constrictor response to bradykinin, but not that to the thromboxane-mimetic U46619 (9,11-dideoxy-ll alpha,9 alpha-epoxymethano-prostaglandin F2.).Moreover, ramiprilat but not RA-octyl caused a concentration-dependent, B2-receptor antagonist sensitive increase in tone when administered alone.7. These findings suggest that an interaction of ACE inhibitors with the B2-receptor or its signal transduction pathway rather than an accumulation of bradykinin within the vascular wall is responsible for the restoration of the endot

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Vessels; Epoprostenol; Female; In Vitro Techniques; Isoquinolines; Jugular Veins; Male; Oligopeptides; Prostaglandin Endoperoxides, Synthetic; Rabbits; Ramipril; Receptors, Bradykinin; Tetrahydroisoquinolines; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation