Vol. 285, Issue 2, 546-552, May 1998

Open State Block by Fendiline of L-Type Ca⁺⁺ Channels in Ventricular Myocytes from Rat Heart¹

Hermann Nawrath, Gunnar Klein, Johanna Rupp, Jörg W. Wegener and Asher Shainberg

Pharmakologisches Institut der Universität Mainz, Obere Zahlbacher Str. 67, D-55101 Mainz, Germany (H.N., G.K., J.R., J.W.W.) and Otto Meyerhoff Center, Department of Life Sciences, Bar-Ilan University, 52900 Ramat-Gan, Israel (A.S.)

The effects of fendiline on L-type Ca⁺⁺ currents [I_Ca(L)] were investigated in rat ventricular cardiomyocytes using the patch-clamp technique both in the whole-cell disrupted-patch and in the cell-attached configuration. For comparison, the effects of verapamil were also investigated. Both compounds depressed the magnitude of whole cell I_Ca(L), verapamil being about 15 times more potent than fendiline. Verapamil did not change the time course of the current, whereas fendiline accelerated its decay when either Ca⁺⁺ or Ba⁺⁺ ions were used as charge carriers. In the presence of the Ca⁺⁺ agonist BayK8644 (10 µM), the potency ratio of fendiline/verapamil was inverted. BayK8644 (10 µM) also reversed the potency ratio of verapamil/fendiline in smooth muscle, with respect to changes in tension induced by K⁺ (48 mM). In single channel recordings at 0.1 Hz, in the presence of BayK8644 (1 µM) and using Ba⁺⁺ ions as the charge carrier, fendiline (1 µM) reduced mean open time by 34% and channel availability by 8%; the ensemble average current of Ca⁺⁺ channels was reduced by 43%. In the same experimental conditions, verapamil (1 µM) was ineffective. These results can be explained by the assumption that fendiline blocks Ca⁺⁺ channels preferentially in the open state, in contrast to verapamil which blocks preferentially inactivated Ca⁺⁺ channels.