Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia‐induced arrhythmias and platelet aggregation in anaesthetized rabbits

Abstract

IThe aim of this study was to compare the effects of the non-selective phosphodiesterase (PDE) inhibitor, isobutylmethylxanthine (IBMX) and the selective PDE III inhibitor, milrinone, in a rabbit model of acute myocardial ischaemia. 2 Coronary artery occlusion caused changes in the ST-segment of the ECG and ectopic activity in all control rabbits. Ventricular fibrillation occurred in 10 out of 14 (71%) of these animals. Pretreatment with IBMX 1004ugkg-1 plus 1O0gkg-1min-', starting 10min before coronary artery occlusion, reduced ischaemia-induced ST-segment changes and ventricular fibrillation occurred in only 10% of this group (n = 10). A similar dose of milrinone had no antiarrhythmic activity, whereas with a lower dose of milrinone, 30 Mgkg-I plus 3 Mgkg' min' (n = 10), only 30% of rabbits fibrillated and ST-segment changes were attenuated. 3 Acute administration of both IBMX and milrinone reduced arterial blood pressure. With the higher dose of milrinone a significant effect was still present after 10min of drug infusion. A greater hypotensive response to the higher dose of milrinone was observed in the rabbits which subsequently fibrillated during ischaemia. A marked tachycardia was also observed after administration of the higher dose of milrinone. 4 At the end of the experiment platelet aggregation was studied ex vivo. ADP-induced aggregation was reduced by pretreatment of the rabbits with milrinone but not IBMX. Both PDE inhibitors enhanced the ability of isoprenaline to inhibit ADP-induced platelet aggregation but milrinone was more effective, particularly at the higher dose. 5 The results demonstrate that IBMX was antiarrhythmic but that this activity was not directly related to inhibition of platelet aggregation. Adverse haemodynamic effects may explain the failure of milrinone to have similar activity during myocardial ischaemia.

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

“…Both clinical and experimental studies have suggested that PDE III inhibitors such as amrinone and milrinone can have arrhythmogenic effects during myocardial ischaemia or reperfusion (Collucci et al, 1986;Lukas & Ferrier, 1988;Lynch et al, 1989). Although we did not see any significant arrhythmogenic activity with milrinone in our previous study in rabbits (Holbrook & Coker, 1989) it is possible that a higher dose may have exacerbated arrhythmias. The doses of rolipram used in the present study were chosen on the basis of its reported relative potency as an inhibitor of certain PDE isoenzymes and from preliminary experiments on its effects on heart rate, arterial blood pressure and LVdP/dtmax in anaesthetized rabbits in our laboratory.…”

“…The doses of rolipram used in the present study were chosen on the basis of its reported relative potency as an inhibitor of certain PDE isoenzymes and from preliminary experiments on its effects on heart rate, arterial blood pressure and LVdP/dtmax in anaesthetized rabbits in our laboratory. Although rolipram is slightly less potent as an inhibitor of PDE IV than milrinone is as an inhibitor of PDE III (Beavo, 1988), we decided to use rolipram in the same doses that we had used milrinone previously (Holbrook & Coker, 1989). A major reason for this decision was that we wanted to avoid causing large reductions in arterial pressure with rolipram because we had evidence that the rabbits which received milrinone and subsequently fibrillated during myocardial isch- aemia were those in which milrinone caused greater decreases in blood pressure (see Holbrook & Coker, 1989).…”

“…We have demonstrated previously that the non-selective phosphodiesterase (PDE) inhibitor isobutylmethylxanthine (IBMX) had antiarrhythmic activity in anaesthetized rabbits subject to acute coronary artery occlusion, whereas the selective PDE III inhibitor, milrinone had no significant antiarrhythmic effects (Holbrook & Coker, 1989). Although the mechanism(s) responsible for the antiarrhythmic action of IBMX could not be determined from this previous study, alterations in platelet aggregation did not seem to be directly relevant since milrinone had greater anti-platelet activity than IBMX.…”

Failure of nitric oxide donors to alter arrhythmias induced by acute myocardial ischaemia or reperfusion in anaesthetized rats

“…Previously, one conclusion that was drawn from studies with certain phosphodiesterase inhibitors was that increasing cardiac cyclic GMP may be antiarrhythmic (Holbrook & Coker, 1989). Although we have performed further studies with phosphodiesterase inhibitors, no firm conclusions about the possible influence of cyclic GMP on arrhythmias could be drawn from these experiments because we could not detect selective increases in cardiac cyclic GMP without concomitant increases in adenosine 3':5'-cyclic monophosphate (cyclic AMP) (Barnes, 1993).…”

The thrombolytic effect of aspirin in animal model

“…Here the sign + indicate, the mice survived at least 5 days optimal dose of the compound in the circulation achieved through oral administration of aspirin is not known. In the initial phase of the study anesthetic agents are not used for their well known antiplatelet and other hematologic effects [35,36], in latter part of the study it was found that to minimize the pain and suffering, the use of morphine sulfate (200 lg/kg body weight) in these animal model did not interfere with the effect of aspirin in thrombolysis.…”