Actions of cardiac drugs on a calcium-dependent potassium channel in hippocampal neurons

JG McLarnon and XP Wang

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.

The patch-clamp method has been used to determine the actions of three newly synthesized cardiac drugs on a calcium-dependent potassium channel, K(Ca), in CA1 hippocampal neurons. Activation of a 65-pS channel was evident in excised inside-out patches with the internal side of the membrane exposed to Ca2+ (0.2 mM); cessation of channel activity was immediate upon perfusion with ethylene glycol bis(beta- aminoethyl ether)-N,N,N',N'-tetraacetic acid-containing solution. In the presence of low concentrations (0.1-10 microM) of the drugs UK- 68798, KC-8857 (tedisamil), or WY-48986 (risotilide), channel openings evinced rapid flickering behavior from open to nonconducting levels; current amplitude was not affected by the drugs. The actions of the drugs were consistent with a voltage-independent block of open K(Ca) channels. In addition, the three drugs, at concentrations similar to those applied to inside-out patches, also blocked K(Ca) when they were applied to the bath solution for outside-out patches. The potencies for channel block of the drugs acting either externally or internally were in the order UK-68798 greater than tedisamil greater than risotilide, with UK-68798 reducing the mean open time of K(Ca) by one-half at a concentration near 0.4 microM.

Volume 39, Issue 4, pp. 540-546, 04/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics