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

Abstract

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.

Figure 1

Change in coronary flow (A), PR interval (B) QT interval (C) and heart rate (D) induced by switching from control solution to intervention 5 min before the start of ischaemia. Values are changes measured at 1 min before the start of ischaemia. ^*P<0.05 versus 0  nM group (time matched control).

Figure 2

Pre-drug (baseline) left ventricular developed pressure in hearts perfused with different K⁺ concentrations (A), and changes in developed pressure following introduction of drug solutions in hearts perfused with 3 mM K⁺ solution (B), with 6 mM K⁺ solution (C) or with 10 mM K⁺ solution (D). Values are mmHg (A) or changes measured 4 min after the introduction of each drug solution (B–D). ^*P<0.05 versus 0  nM group (time matched control).

Figure 3

Pre-drug (baseline) left ventricular diastolic pressure in hearts perfused with different K⁺ concentrations (A), and changes in diastolic pressure following introduction of drug solutions in hearts perfused with 3 mM K⁺ solution (B), with 6 mM K⁺ solution (C) or with 10 mM K⁺ solution (D). Values are mmHg (A) or changes measured 4 min after the introduction of each drug solution (B–D). ^*P<0.05 versus 0  nM group (time matched control).

Figure 4

Pre-drug (baseline) coronary flow in hearts perfused with different K⁺ concentrations (A), and changes in flow following introduction of drug solutions in hearts perfused with 3 mM K⁺ solution (B), with 6 mM K⁺ solution (C) or with 10 mM K⁺ solution (D). Values are ml min g⁻¹ (A) or changes measured 4 min after the introduction of each drug solution (B–D). ^*P<0.05 versus 0  nM group (time matched control).