Mechanism of L- and T-type Ca2+ channel blockade by flunarizine in ventricular myocytes of the guinea-pig.

Flunarizine is a substance known to block voltage-dependent Ca2+ channels in smooth muscle and neuronal cells. Reports on the effect on voltage-dependent cardiac Ca2+ channels are however sparse. Therefore, the mechanism of action of flunarizine on two types of voltage-dependent cardiac Ca2+ channels, the L- and T-type, in single ventricular myocytes of the guinea-pig was investigated using the whole-cell voltage clamp technique. Both channel types can be blocked by flunarizine in a time-, frequency-, voltage-, Ca(2+)-, and proton-dependent way. While the overall mechanism of action on cardiac myocytes is similar to the one reported for other cell types, we found that cardiomyocytes are less susceptible to block (Kd 3.3-11 mM). We also describe a complete analysis of the different components of block, together with evidence for open channel state block and drug-induced changes in channel gating. These findings provide new insights into the mechanism of action of flunarizine on voltage-dependent Ca2+ channels.