Cyclooxygenase Inhibition Converts the Effect of Nitric Oxide Synthase Inhibition from Infarct Size Reduction to Expansion in Isolated Rabbit Hearts

Nitric oxide (NO) and prostacyclin (PGI2) are putative cardioprotective agents. Evidence indicates that there may be a reciprocal relationship involved in the synthesis of NO and PGI2, so that inhibiting the release of one mediator may promote the synthesis of the other. Therefore, we investigated the effects of concomitantly inhibiting NO and PGI2synthesis, using NG-nitro- -arginine ( -NOARG) or indomethacin, respectively, on infarct size. Langendorff-perfused rabbit hearts were assigned randomly to one of five treatment groups of n=6: control -NOARG 100 μ mol/l; indomethacin 3 μ mol/l -NOARG 100 μ mol/l + indomethacin 3 μ mol/l; or -NOARG 100 μ mol/l + -arginine 1 mmol/l. After 30 min regional ischaemia and 120 min reperfusion, infarct size was assessed by tetrazolium staining. Infarct size was reduced significantly in hearts treated with -NOARG (20.8±1.3%) compared to control hearts (34.7±0.4%). This reduction in infarct size was abolished by co-perfusing with a 10-fold excess of -arginine (30.7±1.7%). While indomethacin alone had no effect (33.4±2.3%), perfusion with both -NOARG and indomethacin resulted in a significant increase in infarct size (44.0±1.9%) compared to controls. Treatment with -NOARG alone increased 6-keto PGF1αin coronary effluent prior to ischaemia (30.5±1.2 vs 16.6±1.3 pg/min/g in controls, P<0.05). This effect was reversed by co-perfusion with either -arginine or indomethacin. These results indicate that the reduction in infarct size by -NOARG may be due to increased PGI2release. Concomitant administration of indomethacin negated this effect and revealed an adverse effect of NO synthase inhibition on infarct size.