Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart

1 Mibefradil was compared with (+/-)-verapamil for effects on ischaemia- an d reperfusion-induced ventricular fibrillation (VF), and the role of ischae mia-selective L-channel block was examined. Langendorff perfused rat hearts (n = 12/group) were used. 2 Neither drug at up to 100 nM reduced the incidence of VF during 30 min re gional ischaemia. 300 and 600 nM (+/-)-verapamil abolished VF (P<0.05); mib efradil was effective only at 600 nM (P<0.05). Reperfusion-induced VF incid ence was reduced only by 600 nM (+/-)-verapamil (P<0.05). Both drugs at gre ater than or equal to 100 nM increased coronary flow (P<0.05) with a simila r potency and maximum effectiveness. 3 In separate hearts perfused with Krebs' solution containing 3 mM K+ (the same as that used for arrhythmia studies) neither drug at up to 600 nM affe cted ventricular contractility. With K+ raised to 6 mM, (+/-)-verapamil gre ater than or equal to 30 nM reduced developed pressure (P<0.05); mibefradil did so only at 600 nM (P<0.05). With K+ raised to 10 mM the effects of (+/ -)-verapamil were further increased (P<0.05) and mibefradil became active a t greater than or equal to 100 nM (P<0.05). Likewise both drugs impaired di astolic relaxation, with raised K+ exacerbating the effects and (+/-)-verap amil being more potent and its effects more greatly exacerbated by K+. In c ontrast, when K+ was normal (3 mM), coronary flow was increased by each dru g at greater than or equal to 30 nM (P<0.05) indicating a marked vascular:m yocardial selectivity. 4 In conclusion, mibefradil differed from (+/-)-varapamil in its myocardial effects only in terms of its lower potency. As mibefradil is the more pote nt T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic mil ieu determine the ability of both drugs to block myocardial L-channels; thi s is sufficient to account for the drugs' actions on VF. Neither drug posse sses sufficient selectivity for ischaemic myocardium versus blood vessels t o permit efficacy (VF suppression without marked vasodilatation) and so ina ppropriate hypotension is likely to preclude the safe use of mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical eff ectiveness of (+/-)-verapamil.