THE ROLE OF BRADYKININ AND NITRIC-OXIDE IN THE CARDIOPROTECTIVE ACTION OF ACE-INHIBITORS

Background. The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/repe rfusion injury. The objective of these investigations was to examine t he roles of bradykinin, angiotensin II, and nitric oxide in the cardio protective effects of ramiprilat. Methods. Anesthetized, open-chest ra bbits were instrumented for production of myocardial ischemia (30 minu tes) and subsequent reperfusion (120 minutes), after which myocardial infarct size was measured. Animals were treated intravenously with eit her saline solution, ramiprilat (50 mu g/kg), the bradykinin, receptor antagonist HOE 140 (1 mu g/kg), ramiprilat + HOE 140, angiotensin II (2.5 ng.kg(-1).min(-1)), the angiotensin II receptor antagonist losart an (20 mg/kg), ramiprilat + angiotensin II, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (100 mu g.kg(-1).min(-1)), or ramiprilat + N-G-nitro-L-arginine methyl ester. Results. Among all treatment groups myocardial infarct size was reduced significantly bel ow saline control only by ramiprilat (-54%) and ramiprilat + angiotens in II (-37%). Pretreatment with HOE 140 or N-G-nitro-L-arginine methyl ester abolished the cardioprotective effect of ramiprilat. Neither st imulation nor antagonism of angiotensin II receptors altered infarct s ize from the saline control level. Also, when isolated neonatal rat ca rdiomyocytes were exposed to hypoxia/reoxygenation, ramiprilat (100 mu mol/L) and bradykinin (10 nmol/L) improved cell viability (approximat e to 60%), and the protective effect of both agents was reversed by ad ministration of HOE 140 (10 mu mol/L). Conclusions. These results indi cate that the in vivo cardioprotective effect of ramiprilat can be abo lished by antagonizing bradykinin receptors or inhibiting nitric oxide synthase, and that the effect is not related to angiotensin II recept or activity. The potential bradykinin-sparing property of ramiprilat m ay promote increased bradykinin-stimulated nitric oxide production lea ding to cardioprotection. Part of the cardioprotective effects of rami prilat/bradykinin/nitric oxide may occur locally as demonstrated by th e in vitro results using isolated cardiomyocytes.