Effects of calcium channel blockers on cloned cardiac K+ channels I-kr andI-ks

Cloned HERG and KvLQT1-IsK K+ channels have been expressed in mammalian cel ls and assayed as a target for calcium channel blockers. These channels gen erate the rapid and slow components of the cardiac delayed rectifier K+ cur rent, and mutations can affect them that lead to long QT syndromes. HERG is blocked. by bepridil (EC50=0.55 mu M), verapamil (EC50=0.83 mu M) and mibe fradil (EC50=1.43 mu M), whereas nitrendipine and diltiazem have negligible effects. Steady-state activation and inactivation parameters are shifted t o more negative values in the presence of the blockers. Similarly, KvLQT1-I sK. is inhibited by bepridil (EC50= 10.0 mu M) and mibefradil (EC50=11.8 mu M), whilst being insensitive to nitrendipine, diltiazem or verapamil. This work may help to understand the mechanisms of action of verapamil in certa in ventricular tachycardias as well as some of the deleterious adverse card iac events associated with bepridil and mibefradil.