1.
Mibefradil was compared with (+/-)-
verapamil for effects on ischaemia- and reperfusion-induced
ventricular fibrillation (VF), and the role of ischaemia-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 regional ischaemia. 300 and 600 nM (+/-)-
verapamil abolished VF (P<0. 05);
mibefradil was effective only at 600 nM (P<0.05). Reperfusion-induced VF incidence was reduced only by 600 nM (+/-)-
verapamil (P<0.05). Both drugs at >/=100 nM increased coronary flow (P<0.05) with a similar 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 affected ventricular contractility. With K+ raised to 6 mM, (+/-)-
verapamil >/=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 at >/=100 nM (P<0.05). Likewise both drugs impaired diastolic relaxation, with raised K+ exacerbating the effects and (+/-)-
verapamil being more potent and its effects more greatly exacerbated by K+. In contrast, when K+ was normal (3 mM), coronary flow was increased by each
drug at >/=30 nM (P<0.05) indicating a marked vascular : myocardial selectivity. 4. In conclusion,
mibefradil differed from (+/-)-
verapamil in its myocardial effects only in terms of its lower potency. As
mibefradil is the more potent T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic milieu determine the ability of both drugs to block myocardial L-channels; this is sufficient to account for the drugs' actions on VF. Neither
drug possesses sufficient selectivity for ischaemic myocardium versus blood vessels to permit efficacy (VF suppression without marked vasodilatation) and so inappropriate
hypotension is likely to preclude the safe use of
mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical effectiveness of (+/-)-
verapamil.