Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs.
Cloned HERG and KvLQT1-IsK K+ channels have been expressed in mammalian cells and assayed as a target for calcium channel blockers. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them that lead to long QT syndromes. HERG is blocked by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM) and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady-state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1-IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), whilst being insensitive to nitrendipine, diltiazem or verapamil. This work may help to understand the mechanisms of action of verapamil in certain ventricular tachycardias as well as some of the deleterious adverse cardiac events associated with bepridil and mibefradil.
Chouabe
C
C
Institut de Pharmacologie Moléculaire et Cellulaire-CNRS, Valbonne, France.
Drici
M D
MD
Romey
G
G
Barhanin
J
J
D000818:Animals; D019556:COS Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D027682:Cation Transport Proteins; D003001:Cloning, Molecular; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000187:drug effects*; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated
D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated