Effect of Verapamil Enantiomers and Metabolites on Cardiac K⁺ Channels Expressed in <i>Xenopus</i> Oocytes

Abstract

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 μM (n = 4), 5.1 ± 0.5 μM (n = 6), 161.0 ± 26.3 μM (n = 4), and 3.8 ± 0.2 μM (n = 5), respectively. The same potency of HERG channel inhibition was observed for the optical enantiomers (+)-verapamil (IC₅₀ = 3.5 ± 0.4 μM, n = 5) and (–)-verapamil (IC₅₀ = 4.0 ± 0.7 μM, n = 4), as well as the derivatives norverapamil (D591; IC₅₀ = 3.8 ± 0.3 μM, n = 4) and D703 (IC₅₀ = 2.2 ± 0.4 μM, n = 4). The verapamil metabolites D620 and D617 did not block HERG-induced currents at concentrations of up to 30 μM (n = 3). These results demonstrate that cardiac delayed rectifier potassium currents are sensitive targets to calcium channel blockers.

Verapamil Inhibits Proliferation of LNCaP Human Prostate Cancer Cells Influencing K+ Channel Gating

“…Furthermore, no indication of the C-type inactivation, characteristic of other types of verapamil-sensitive K ϩ channels, has been observed in LNCaP cell I K . Verapamil inhibited I K in LNCaP cells with an IC 50 value of 11 M. This value is close to those previously reported for transfected Kv1.3 (Rauer and Grissmer, 1996) and Kv1.1 (Waldegger et al, 1999) channels, as well as for delayed K ϩ channels in rat intracardiac neurons (Hogg et al, 1999).…”

“…First, verapamil reduced I K without changing its macroscopic kinetics. Verapamil did not produce the expected apparent "inactivation" of I K in LNCaP cells analogous to the previously reported acceleration of I K inactivation in other cell models (DeCoursey, 1995;Rauer and Grissmer, 1996;Trequattrini et al, 1998;Waldegger et al, 1999;Zhang et al, 1999), considered as a time-dependent interaction of verapamil with open K ϩ channels. Second, the verapamil-produced inhibition of K ϩ channels was not use-dependent: the initial I K evoked after Ϸ30 s preincubation with verapamil solution was inhibited to its steady-state level, indicating that verapamil interacted with the resting form of the channel.…”

IonWorks™ HT: A New High-Throughput Electrophysiology Measurement Platform

“…These values compare favorably with reported pIC 50 . [14][15][16][17][18][19][20][21] In both experiments, pIC 50 values were readily obtained from each plate, confirming that the 4 PatchPlate™ wells per compound concentration are adequate to define precise pharmacology. As a measure of interplate variability, the same compound plates were screened on a second occasion on different PatchPlates™.…”

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

“…The slow component of the delayed rectifier potassium current (I Ks ) was recuced by 18 and 40 % in the presence of 1 and 5 µM verapamil, respectively [149]. Verapamil exerted an inhibitory action on expressed potassium channel proteins including human ether-a-go-go (hERG) channels in the possible therapeutic level in the myocardium [150], [151] and K v 1.5 (responsible for I Kur ) channels with an IC 50 of 5.1 µM [151].The native current of I Kur was also blocked by verapamil in human atrial cells from as low as 1 µM [122]. Verapamil blocked I K,Na in guinea-pig ventricular cells with an IC 50 of 3.36 µM [127].…”