Effect of verapamil enantiomers and metabolites on cardiac K+ channels expressed in Xenopus oocytes.
The effect of verapamil and its enantiomers and metabolites on cardiac action potential repolarizing potassium channels was tested. For this purpose, the potassium channels Kv1.1, Kv1.5, Kir2.1, and HERG, and the IsK subunit of the IKs-channel complex were expressed in Xenopus oocytes and two-electrode voltage-clamp experiments were performed. Verapamil induced a concentration-dependent block of Kv1. 1-, Kv1.5-, IKs-, and HERG-induced currents with IC50 values of 14.0 +/- 2.7 microM (n = 4), 5.1 +/- 0.5 microM (n = 6), 161.0 +/- 26.3 microM (n = 4), and 3.8 +/- 0.2 microM (n = 5), respectively. The same potency of HERG channel inhibition was observed for the optical enantiomers (+)-verapamil (IC50 = 3.5 +/- 0.4 microM, n = 5) and (-)-verapamil (IC50 = 4.0 +/- 0.7 microM, n = 4), as well as the derivatives norverapamil (D591; IC50 = 3.8 +/- 0.3 microM, n = 4) and D703 (IC50 = 2.2 +/- 0.4 microM, n = 4). The verapamil metabolites D620 and D617 did not block HERG-induced currents at concentrations of up to 30 microM (n = 3). These results demonstrate that cardiac delayed rectifier potassium currents are sensitive targets to calcium channel blockers.
Department of Physiology, University of Tübingen, Deutschland.
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S
Waldegger
G
G
Niemeyer
K
K
Mörike
C A
CA
Wagner
H
H
Suessbrich
A E
AE
Busch
F
F
Lang
M
M
Eichelbaum
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006321:Heart / Q000502:physiology*; D051662:Kv1.1 Potassium Channel; D051666:Kv1.5 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D051662:Kv1.1 Potassium Channel; C016904:norverapamil; D014700:Verapamil