Briefly after withdrawal of the (T-type) calcium channel blocker mibefradil from 
the market, four cases of life-threatening interaction of mibefradil with 
dihydropyridines were reported. We investigated in vitro whether mibefradil 
interacts with a dihydropyridine, as described for other non-dihydropyridine 
compounds. Rat working hearts were used to examine functional interactions 
between amlodipine and mibefradil. Gallopamil and another T-type-channel 
blocker, ethosuximide, were included for comparison. Effects of mibefradil, (+)- 
and (-)-gallopamil on [3H](+)-isradipine binding were studied in membranes from 
tsA201-cells transfected with alpha(1c)-, alpha(2)delta-, and beta(1a)- or 
beta(2a)-calcium channel subunits. Mibefradil increased negative inotropic 
effect of amlodipine, but not of gallopamil. Gallopamil and ethosuximide showed 
no influence on contractile effects of amlodipine. Furthermore, mibefradil 
concentration-dependently caused bradycardic rhythm disturbance. The same type 
of arrhythmia was observed combining low concentrations of mibefradil with 
amlodipine, or with gallopamil, respectively. Amlodipine alone, or the 
combination of gallopamil or ethosuximide with amlodipine did not cause any 
arrhythmia. Binding studies showed a concentration-dependent positive allosteric 
interaction between [3H](+)-isradipine and mibefradil, but not with 
[3H](+)-isradipine and gallopamil enantiomers. Molecular and functional evidence 
points to an interaction between a dihydropyridine and mibefradil. Mibefradil 
caused rhythm disturbances and potentiation of negative inotropy when combined 
with amlodipine.