Cocaine blockade of the acetylcholine-activated muscarinic K+ channel in ferret cardiac myocytes

The effects of cocaine on the acetylcholine(ACh)-activated muscarinic K+ current (I-K(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 I-K(ACh) is almost 5 times greater in atrial cells than in left ventricular myocytes. Cocaine reversibly blacked I-K(ACh) in a dose-dependent manner. Methylecgonidine (MEG), the major product of pyrolysis of cocaine base, also produced similar effects on I-K(ACh). The concentration to produce 50% inhibition of I-K(ACh) was 25 mu M and 12 mu M for cocaine and MEG, respectively. Cocaine at micromolar concentrations also significantly inhibited the adenosine-activated purinergic K+ current (I-K(Ado)) which has the same electrophysiological properties as I-K(ACh). Furthermore, cocaine inhibited I-K(ACh) activated by GTP gamma S, which evokes I-K(ACh) by bypassing the muscarinic receptor and directly activating the G-protein, G(K). These results suggest that cocaine-induced suppression of I-K(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.