Effects of zaprinast and rolipram on platelet aggregation and arrhythmias following myocardial ischaemia and reperfusion in anaesthetized rabbits

Abstract

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 pg kg' plus 30jug kg' min-) had no significant effect on ischaemia-or reperfusion-induced ST-segment changes, or arrhythmias. In contrast, rolipram (30 pg kg-1 plus 3jug kg-1 min -') and (100 ug kg-' plus l0 pug kg-' min-') 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/dtmax 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.

Altered relationship between cyclic GMP and myocardial O2 consumption in renal hypertension-induced cardiac hypertrophy

“…We used zaprinast, a selective cyclic GMP-phosphodiesterase inhibitor [8,14,29], to test this hypothesis. This agent was applied topically to the heart in order to avoid systemic effects in anesthetized open-chest rabbits.…”

An endogenous protectant effect of cardiac cyclic GMP against reperfusion‐induced ventricular fibrillation in the rat heart

“…More recently, Mizumura & Gross (1995) have shown that the cardioprotective effects of nitroglycerin are prevented by methylene blue in the anaesthetized dog. In contrast, Holbrook & Coker (1991) and recently Barnes & Coker (1995) have used phosphodiesterase inhibitors and NO donors to increase cardiac cyclic GMP levels selectively in anaesthetized rats. However, neither group of drugs had any effect on reperfusion-induced arrhythmias following 25 min of coronary artery occlusion.…”

Cardiac Cyclic Nucleotide Phosphodiesterases: Function, Regulation, and Therapeutic Prospects

“…In experimental animals, pharmacologic inhibition of PDE4 has been shown to potentiate cardiac arrhythmias induced by adrenergic stimulation [52], exercise [65], or myocardial ischemia/reperfusion [82]. Genetic depletion of PDE4D in mice results in delayed after depolarization formation, exercise induced arrhythmias, and sudden death [83,84].…”