Cyclooxygenase-1 and-2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning

Background-The purpose of this study was to examine the effects of cyclooxy genase (COX) deficiency on baseline functional characteristics and on recov ery of left ventricular developed pressure (LVDP) after 20 minutes of globa l ischemia and 40 minutes of reperfusion in untreated and preconditioned he arts. Methods and Results-Compared with hearts from wild-type (WT) and COX-2(-/-) mice, baseline cardiac prostaglandin (PG) E-2 and 6-keto-PGF(1 alpha) leve ls were significantly decreased in hearts from COX-1(-/-) mice. After ische mia, cardiac PGE(2) levels increased in WT, COX-1(-/-), and COX-2(-/-) mice (P <0.05). Recovery of function (LVDP) after global ischemia in hearts fro m COX-1(-/-) and COX-2(-/-) mice was significantly less than in WT hearts. Pretreatment of WT mice with indomethacin for 2 days before ischemia signif icantly decreased LVDP recovery; however, perfusion of WT hearts with indom ethacin for 40 minutes before ischemia did not significantly alter LVDP rec overy, Postischemic recovery of LVDP in COX-1(-/-) and COX-2(-/-) was uncha nged by perfusion with 5 mu mol/L PGE(2), PGD(2), PGF(2 alpha), or carbopro stacyclin. Hearts from COX-2(-/-) mice showed an increase in ischemic contr acture compared with hearts from WT and COX-1(-/-) mice; however, hearts di d not differ in intracellular pH, ATP, or inorganic phosphate during ischem ia. Ischemic preconditioning significantly improved postischemic LVDP recov ery in COX-1(-/-), COX-2(-/-), and WT mice. Conclusions-Genetic disruption or 2-day chemical inhibition of COX-1 and CO X-2 decreases recovery of LVDP after ischemia; however, acute perfusion wit h indomethacin is not detrimental. These data are consistent with protectio n due to the altered expression of some protein that is modulated by COX or its metabolites.