Biochemical and biophysical studies of the interaction of class I antiarrhythmic drugs with the cardiac sodium channel

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AbstractClass I antiarrhythmic drugs block the cardiac sodium channel and are now used widely for a variety of cardiac arrhythmias. The nature of the interaction of the drugs with these channels, and their mechanism of action, have been areas of considerable recent interest. Here we review several aspects of drug action. Evidence that sodium channel blockade itself is antiarrhythmic arises from experiments in which the sodium channel‐specific toxin tetrodotoxin was shown to prevent ventricular fibrillation in rabbit hearts. A radioligand binding assay for the cardiac sodium channel was then developed using [3H]Batrachotoxinin (BTX) Benzoate and freshly isolated rat cardiac myocytes. Class I antiarrhythmic drug binding identified in this model fits conventional criteria for binding to a receptor. This receptor behaves like an allosteric protein; class I antiarrhythmic drugs appear to bind to and stabilize closed channels. The mechanism of drug binding and electrophysiologic consequences have been examined in a number of model systems by microelectrode studies, whole cell voltage clamping, and more recently voltage clamp studies of single isolated channels in lipid bilayers. Using the latter method, we have shown that lidocaine causes two distinct kinds of sodium channel blockade. The first is a very slow block which can be demonstrated with simple aryl compounds. The second kind of block is a very rapid block which can also be caused by simple alkyl amines. Thus, the two major structural moieties of lidocaine each cause a specific form of block. The structure‐activity relationships of class I drugs were explored with homologs of lidocaine in the radioligand binding assay. With this method the existence of a number of receptor subdomains has been demonstrated, each of which recognizes specific structural moieties of class I drugs. Finally, we have explored both drug proarrhythmia and drug resistance. Drug proarrhythmia may be due to homogeneous slowing of conduction with little effect on refractoriness. One form of drug resistance may be due to induction of synthesis of new cardiac sodium channels by exposure to animals with chronic class I drug administration. Mexiletine induces a three‐fold increase in rat cardiac sodium channels within 3 days due to increased sodium channel mRNA synthesis. Thus drug resistance might be due to drug‐induced increases in the numbers of cardiac sodium channels. © 1994 Wiley‐Liss, Inc.