Cardioprotective actions of bradykinin in myocardial ischemia and left ventricular hypertrophy.
To delineate the cardioprotective actions of bradykinin (BK) and the contribution of endogenous kinins to the cardiac effects of the ACE inhibitor ramipril, we used the specific B2 kinin receptor antagonist icatibant (HOE 140) during myocardial ischemia and left ventricular hypertrophy (LVH). In isolated working rat hearts, perfusion with ramiprilat (10 nM to 10 microM) reduced the incidence and duration of ventricular fibrillation, and improved cardiodynamics and myocardial metabolism. BK perfusion (0.1 nM to 10 nM) induced comparable cardioprotective effects. In addition, perfusion with ramiprilat (0.1 microM) markedly increased kinin outflow measured by RIA. The beneficial effects of ramiprilat and BK were abolished by the addition of the specific NO synthase inhibitor NG-nitro-L-arginine (L-NNA 1 microM) or icatibant (1 nM). Similar results were obtained in dogs, rabbits and rats with myocardial infarction induced by ligation of the left descending coronary artery. The influence of the icatibant on the antihypertrophic effect of ramipril and BK in the LVH was investigated in rats made hypertensive by aortic banding. Ramipril at the antihypertensive dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and the development of LVH. The lower non-antihypertensive dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and the lower dose of ramipril as well as the antihypertensive action of the higher dose of ramipril were abolished by coadministration of the icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)
Linz
W
W
Hoechst AG, SBU Cardiovascular Agents, Frankfurt (Main), Germany.
Wiemer
G
G
Schölkens
B A
BA
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D019335:Nitroarginine; D017257:Ramipril / Q000494:pharmacology; D051381:Rats
D019335:Nitroarginine; C065679:icatibant; D001120:Arginine; D017257:Ramipril; D001920:Bradykinin