Class I antiarrhythmic drugs: allosteric inhibitors of [3H] batrachotoxinin binding to rat cardiac sodium channels.

This study assessed whether class I antiarrhythmic drugs allosterically inhibit [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTXB) binding to sodium channels on freshly isolated rat cardiac myocytes. All class I drugs tested inhibited equilibrium [3H]BTXB binding in a concentration-dependent manner. Scatchard analysis showed that disopyramide, flecainide, transcainide, lidocaine and amiodarone reduced [3H]BTXB maximum binding (Bmax) whereas procainamide, mexiletine, quinidine, quinine, tocainide, propafenone, encainide and O-demethylencainide increased [3H]BTXB KD but had little effect on Bmax. Kinetic [3H]BTXB binding assays were used to assess the mechanism by which class I drugs inhibit [3H]BTXB binding. Drugs that increase the unidirectional dissociation rate constant (k-1) of [3H]BTXB probably bind to sodium channels to which [3H]BTXB is already bound. Although all class I drugs increased the k-1 of [3H]BTXB, they did so weakly and at concentrations above the IC50 values of the drugs. Thus, drug binding to [3H]BTXB-bound channels does not appear to be the predominant mechanism underlying their ability to inhibit [3H]BTXB binding. Conversely, drugs which allosterically decrease the unidirectional association rate constant (K+1) of [3H]BTXB probably bind to channels to which [3H]BTXB is not already bound. All class I drugs decreased the k+1 of [3H]BTXB, indicating drug binding to [3H]BTXB-free channels. The estimated affinities of drugs for [3H]BTXB-free channels correlated closely with the IC50 values of these drugs (r = 0.94, P < .001), suggesting that this effect is a common and major determinant in their ability to inhibit [3H]BTXB binding. The results are discussed in light of electrophysiologic theories of class I antiarrhythmic drug action.