zaprinast and Arrhythmias--Cardiac

This study was designed to compare the haemodynamic, electrophysiological and pharmacodynamic effects of three selective inhibitors of the different isoenzyme forms of phosphodiesterase (PDE) on ischaemia-induced dysrhythmias in the anaesthetized rat. The drugs used were pimobendan, a selective PDE III inhibitor, rolipram, a selective PDE IV inhibitor, and zaprinast, a selective PDE V inhibitor.. The coronary artery was occluded 15 min after commencing drug administration, and myocardial ischaemia was maintained for 30 min during which the heart rate and mean arterial pressure were recorded. cAMP and cGMP were determined by radioimmunoassay.. Pretreatment with rolipram decreased the duration of ventricular tachycardia without any change in the incidences of dysrhythmias or the mortality rate. This drug did not modify ventricular content of adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP). Pimobendan (1 mg kg(-1) + 0.1 mg kg(-1) min) decreased the duration of ventricular tachycardia. This dose of pimobendan and zaprinast (1 mg kg(-1) + 0.1 mg kg(-1) min(-1)) increased the incidence rate of ventricular fibrillation following coronary artery ligation and the mortality rate. Moreover, both drugs increased cGMP in the ventricle.. The results demonstrated that pimobendan and zaprinast increased the incidence of dysrhythmias and the mortality rate, which was accompanied by an increase in the ventricular content of cGMP. Rolipram decreased the duration of ventricular tachycardia without a change in the cyclic nucleotide content or in the mortality rate.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Rate; Heart Ventricles; Ligation; Male; Myocardial Ischemia; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Purinones; Pyridazines; Rats; Rats, Sprague-Dawley; Rolipram

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 micrograms kg-1 plus 30 micrograms kg-1 min-1) had no significant effect on ischaemia- or reperfusion-induced ST-segment changes, or arrhythmias. In contrast, rolipram (30 micrograms kg-1 plus 3 micrograms kg-1 min-1) and (100 micrograms kg-1 plus 10 micrograms 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/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.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Arrhythmias, Cardiac; Coronary Disease; Electrocardiography; Hemodynamics; Myocardial Reperfusion; Platelet Aggregation; Purinones; Pyrrolidinones; Rabbits; Rolipram