Aspirin, but not the more selective cyclooxygenase (COX)-2 inhibitors meloxicam and SC 58125, aggravates postischaemic cardiac dysfunction, independent of COX function

Inhibition of cyclooxygenase (COX) might favour non-enzymatic formation of cardiodepressive isoprostanes from arachidonic acid by radicals generated d uring reperfusion. This could explain deleterious effects of acetylsalicyli c acid (ASA) on cardiac function. We examined the influence of COX inhibiti on on myocardial function after low-flow ischaemia and reperfusion, employi ng either ASA (100 mu mol/l), the partially selective COX-2 inhibitor melox icam (0.3 mu mol/l and 3.0 mu mol/l), or the highly selective COX-2 inhibit or SC 58125 (1.0 mu mol/l and 3.0 mu mol/l). Isolated, buffer-perfused guin ea pig hearts, performing pressure-volume work before and after consecutive low-flow ischaemia and reperfusion, were used for the study. Measurement o f coronary and aortic flow, ejection time and heart rate served to calculat e external heart work (EHW), before and after ischaemia. Additionally, rele ase of prostacyclin and thromboxane A(2), production of lactate, consumptio n of pyruvate and tissue concentration of the isoprostane 8-iso-PGF(2 alpha ), were measured. ASA significantly reduced recovery of EHW (46+/-18% vs. 82+/-15% for contro ls), whereas meloxicam and SC 58125 did not (64+/-15% and 74+/-13% recovery , respectively). Paradoxically, ASA increased reactive hyperaemia and consu mption of pyruvate in the early reperfusion phase in comparison to all othe r groups, while lactate production did not differ. Prostacyclin production did not increase during reperfusion and was not significantly different bet ween groups at any time point. In contrast, thromboxane A(2) release increa sed about fivefold in the 2nd min of reperfusion under control conditions a nd in the presence of SC 58125, but was inhibited by ASA and by meloxicam i n both concentrations. Isoprostane content of heart tissue was not detectab ly influenced under the mild reperfusion conditions used here. We conclude that ASA can aggravate postischaemic cardiac dysfunction, indep endent of COX inhibition. The deleterious effect in the present model might be due to uncoupling of mitochondrial oxidative phosphorylation rather tha n to direct effects of reduced eicosanoid release or radical induced format ion of isoprostanes.