Blockade of cardiac sodium channels by cocaine and its primary metabolites: A possible molecular mechanism for cocaine-related sudden death
Description
Although cocaine-related deaths have increased significantly in the past decade, the mechanism(s) of mortality remain poorly defined. Case reports suggest a cardiovascular etiology (Young and Glauber, 1947; Isner, 1986) with some implicating conduction block (Young and Glauber, 1947; Nanji and Filipenko, 1984) as the underlying cause. Since cocaine is well known to possess potent local anesthetic activity in nerves, one possible mechanism for cocaine cardiotoxicity is the alteration of normal conduction within the heart by block of cardiac sodium channels. The effects of cocaine were therefore examined on cardiac sodium channels in single ventricular myocytes isolated from guinea pigs using the whole cell variant of the patch clamp technique. Cocaine (30-50 $\mu$M) was found to be a potent blocker of cardiac sodium channels at concentrations reportedly achieved following a fatal overdose in man. To examine the role of cocaine-induced cardiac sodium channel block on cardiac conduction in vivo, the effects of cocaine on the electrocardiogram (lead II) were also examined. Cocaine produced conduction disturbances in an anesthetized cat indicative of sodium channel block (widened QRS complex, idioventricular arrhythmias). Since approximately 30% of the cocaine-related deaths occur at a time when an appreciable amount of cocaine can be expected to have been converted to metabolites (2-5 hours after administration), the effects of cocaine's primary metabolites: ecgonine methyl ester, benzoylecgonine, and norcocaine were also examined to see if they possessed sodium channel blocking properties similar to cocaine. Norcocaine was found to be a potent blocker of cardiac sodium channels while ecgonine methyl ester and benzoylecgonine (at 100 $\mu$M) were found to lack cardiac sodium channel blocking ability. Cocaine has also been shown to cause seizures which may result in metabolic and/or respiratory acidosis. The effects of internal and external pH on the cocaine-sodium channel interaction were therefore examined. Open channel block produced by 30 $\mu$M cocaine was enhanced by either an acidic internal pH or a basic external pH. In contrast, the steady-state amount of inactivated channel block was found to be only weakly dependent upon pH. These studies provide a possible molecular mechanism for cocaine-related arrhythmias and sudden death