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Vol. 284, Issue 1, 10-18, 1998

Cocaine Blockade of the Acetylcholine-Activated Muscarinic K+ Channel in Ferret Cardiac Myocytes1

Yong-Fu Xiao and James P. Morgan

The Charles A. Dana Research Institute and The Harvard-Thorndike Laboratory, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

The effects of cocaine on the acetylcholine(ACh)-activated muscarinic K+ current (IK(ACh)) were assessed with the whole-cell patch-clamp technique in single atrial and left ventricular myocytes enzymatically isolated from adult ferret hearts. The density of IK(ACh) is almost 5 times greater in atrial cells than in left ventricular myocytes. Cocaine reversibly blocked IK(ACh) in a dose-dependent manner. Methylecgonidine (MEG), the major product of pyrolysis of cocaine base, also produced similar effects on IK(ACh). The concentration to produce 50% inhibition of IK(ACh) was 25 µM and 12 µM for cocaine and MEG, respectively. Cocaine at micromolar concentrations also significantly inhibited the adenosine-activated purinergic K+ current (IK(Ado)), which has the same electrophysiological properties as IK(ACh). Furthermore, cocaine inhibited IK(ACh) activated by GTPgamma S, which evokes IK(ACh) by bypassing the muscarinic receptor and directly activating the G-protein, GK. These results suggest that cocaine-induced suppression of IK(ACh) is caused by its interactions beyond the binding site of muscarinic receptors. The antimuscarinic effect of cocaine may play an important role in cocaine cardiotoxicity by reducing the membrane electrical stability and acting synergistically with other actions of cocaine to facilitate the occurrence of lethal cardiac arrhythmias.

0022-3565/98/2841-0010$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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