HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers.
We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/IsK K+ channels. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in transfected COS cells, HERG is blocked in a concentration-dependent manner 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), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K+ channels HERG and KvLQT1/IsK, which represent together the cardiac delayed rectifier K+ current, are sensitive targets to calcium channel blockers. This work may help in understanding the mechanisms of action of verapamil in certain ventricular tachycardia, as well as some of the deleterious adverse cardiac events associated with bepridil.
Chouabe
C
C
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Sophia Antipolis, F-06560 Valbonne, France.
Drici
M D
MD
Romey
G
G
Barhanin
J
J
Lazdunski
M
M
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015764:Bepridil / Q000494:pharmacology; D019556:COS Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003001:Cloning, Molecular; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008133:Long QT Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D020748:Mibefradil; D015221:Potassium Channels / Q000145:classification / Q000187:drug effects* / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D015221:Potassium Channels; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D015764:Bepridil; D014700:Verapamil