COX‐1 in Addition to COX‐2 Mediates Ischemic Preconditioning

Abstract

COX-2 is an important mediator of cardiovascular protection after ischemia and reperfusion. It is known that COX-2 has a role in ischemic preconditioning (IP). The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE2 and/or PGI2. Little is known about the actions of COX-1 in IP. This study was designed to determine the effects of COX-1 inhibition on infarct size after IP. Male New Zealand white rabbits were administered SC-560 (0.3 mg/kg or 1 mg/kg), nimesulide (5mg/kg), or vehicle intravenously prior to IP, 30 minutes of ischemia and 4 hours of reperfusion. IP reduced myocardial infarct size (10.5+/−2.6% vs. control 40.4+/−2.6%; p < 0.001) whereas treatment with the COX-2 inhibitor nimesulide abolished the protective effects of IP (40.3+/−3.1% p < 0.001 vs. IP). Treatment with the COX-1 inhibitor SC-560 reduced the protective effects of IP at a dose of 1 mg/kg (30.2+/−2.8%; p < 0.01), but not at 0.3 mg/kg (23.7+/−3.1%). The data suggest that endothelial COX-1 may also play a role in IP. It is likely that COX-2 plays a larger role because of its inducible activation, but the ability of COX-1 to produce protective PGE2 and/or PGI2 should not be overlooked. A recent study (Mitchell et al. 2006) suggests that endothelial COX-1, a source of PGI2, is more susceptible to inhibition by selective COX-2 inhibitors than is platelet COX-1. This would explain the reduced efficacy of IP by both the selective COX-1 and COX-2 inhibitors.