Calcium antagonist clevidipine reduces myocardial reperfusion injury by a mechanism related to bradykinin and nitric oxide.
Certain calcium antagonists, in addition to their classic actions, can increase blood flow during ischemia via bradykinin- and nitric oxide (NO)-dependent mechanisms and protect the ischemic myocardium against reperfusion injury by enhancing NO bioavailability. The current study aimed to investigate the possible involvement of bradykinin and NO in the cardioprotective action of the short-acting calcium antagonist clevidipine during late ischemia and reperfusion. Anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Four groups were given vehicle, clevidipine, clevidipine in combination with the bradykinin B2 receptor antagonist HOE 140 or clevidipine in combination with HOE 140 and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) into the LAD during the last 10 min of ischemia and the first 5 min of reperfusion. There were no significant differences in hemodynamics among the groups before ischemia or during ischemia-reperfusion. The infarct size (IS) was 87% +/- 2% of the area at risk in the vehicle group. Clevidipine reduced the IS to 60% +/- 3% (p < 0.001 vs vehicle). When clevidipine was administered together with HOE 140, the protective effect of clevidipine was abolished (IS, 80% +/- 3%; p < 0.001 vs clevidipine), whereas addition of SNAP restored cardioprotection (IS, 62% +/- 5%; p < 0.001 vs vehicle). The increase in LAD blood flow by endothelium-dependent dilator substance P was significantly larger in the clevidipine group than in the other groups. The results suggest that the cardioprotective effect of clevidipine during late ischemia and early reperfusion is mediated via bradykinin- and NO-related mechanisms.
D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D065168:Bradykinin Receptor Antagonists; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D013552:Swine
D065168:Bradykinin Receptor Antagonists; D002121:Calcium Channel Blockers; D020030:Nitric Oxide Donors; D011725:Pyridines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C118563:clevidipine; D009569:Nitric Oxide; D001920:Bradykinin