The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs

Abstract

The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs. In closed chest pigs (n = 4), R75231 exerted a moderate dose‐dependent decrease in mean arterial blood pressure (from 97 ± 4 mmHg to 95 ± 4, 90 ± 1 and 83 ± 2 mmHg at 25, 50 and 100 μg kg−1 respectively) and produced a dose‐related shift to the left of the blood pressure dose‐response curve to intravenous bolus doses of adenosine. The degree of inhibition of adenosine uptake by R75231, assessed ex vivo in erythrocyte suspensions, was 43 ± 5%, 64 ± 13 and 114 ± 15% at doses of 25, 50 and 100 μg kg−1 respectively. In open chest pigs, intravenous injection of R75231 (50 μg kg−1; n = 6 and 100 μg kg−1; n = 10) induced a dose‐related decrease in both systolic and diastolic arterial blood pressure which was more marked than in closed‐chest pigs (mean pressure 86 ± 4 to 70 ± 2 mmHg and 88 ± 6 to 60 ± 6 mmHg with 50 and 100 μg kg−1 respectively), without affecting heart rate or myocardial contractility. Coronary artery occlusion in these pigs caused a secondary decrease in blood pressure. This was not observed in controls (n = 10). The lower dose of R75231 did not exert any antifibrillatory effects, whereas the higher dose significantly reduced the incidence of ventricular fibrillation, from 80% in control pigs to 30%. Neither dose modified the incidence of ventricular tachycardia (33% and 40% with 50 and 100 μg kg−1 respectively, compared to 30% in controls) or had any effect on the total number of ventricular ectopic beats (85 ± 47 and 130 ± 31 vs 110 ± 19 in controls). R75231, at a dose of 100 μg kg−1, also attenuated the ischaemia‐induced shortening of QRS‐interval, but neither dose modified the ST‐segment depression seen following occlusion. These results show that the nucleoside transport inhibitor, R75231, exerts an antifibrillatory effect in a model of severe myocardial ischaemia in a dose which completely inhibits adenosine uptake ex vivo. However, while this agent has minimal haemodynamic effects in closed chest animals, the reduction in blood pressure induced by R75231 in open‐chest pigs cannot be excluded as a possible contributory mechanism of the antiarrhythmic effects of this drug. 1993 British Pharmacological Society