EFFECTS OF ZAPRINAST AND ROLIPRAM ON PLATELET-AGGREGATION AND ARRHYTHMIAS FOLLOWING MYOCARDIAL-ISCHEMIA AND REPERFUSION IN ANESTHETIZED RABBITS

1 This study was designed to compare the effects of two selective inhibitors of certain phosphodiesterase (PDE) isoenzymes on arrhythmias induced by coronary artery occlusion and reperfusion. The drugs used were zaprinast which inhibits guanosine 3':5'-cyclic monophosphate (cyclic GMP)-specific PDE (PDE V) and rolipram which inhibits cyclic GMP-insensitive, adenosine 3':5'-cyclic monophosphate (cyclic AMP)-specific PDE (PDE IV). 2 Pretreatment of anaesthetized rabbits with zaprinast (300-mu-g kg-1 plus 30-mu-g kg-1 min-1) had no significant effect on ischaemia- or reperfusion-induced ST-segment changes, or arrhythmias. In contrast, rolipram (30-mu-g kg-1 plus 3-mu-g kg-1 min-1) and (100-mu-g kg-1 plus 10-mu-g kg-1 min-1) increased the severity of arrhythmias. With the higher dose of rolipram, ST-segment changes were increased in magnitude and mortality due to ventricular fibrillation during ischaemia or reperfusion was increased to 80% compared with 30% in controls (n = 10 per group). 3 Zaprinast caused small but significant increases in heart rate and arterial blood pressure whereas rolipram decreased diastolic arterial pressure, increased left ventricular (LV) dP/dt(max) and substantially increased heart rate. 4 At the end of each experiment platelet aggregation was measured ex vivo. Pretreatment of rabbits with either dose of rolipram had no significant effect on platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid or thrombin or on isoprenaline- or prostacyclin-induced inhibition of aggregation. Aggregatory responses to ADP and collagen were increased in platelets obtained from rabbits which had received zaprinast. 5 These results indicate that in the dose used here, the PDE V inhibitor zaprinast had no significant effect on arrhythmias. The effects of the PDE IV inhibitor rolipram on haemodynamics, combined with its lack of antiplatelet activity, may have contributed to the exacerbation of arrhythmias observed during myocardial ischaemia and reperfusion.