Combined effects of different class I antiarrhythmic agents on maximum rate of depolarization (Vmax) of action potentials in guinea-pig papillary muscles.

The combination of two different kinds of class I antiarrhythmic agents (class Ia, Ib, or Ic) was examined with regard to their effects on the maximum rate of depolarization (Vmax) of action potentials in guinea-pig papillary muscles. The combinations of disopyramide plus lidocaine, disopyramide plus mexiletine, mexiletine plus flecainide, and disopyramide plus flecainide were employed to study their effects on use-dependent block of Vmax. All the combinations increased the percent of use-dependent block at most of the frequencies employed (0.1-3.3 Hz) as compared to the effects of the single use of either drug, but no decrease in use-dependent block was found with any of the combinations. The time courses of the development of use-dependent block by disopyramide, lidocaine, and mexiletine were best expressed by two exponential functions, whereas those by flecainide were expressed by a single exponential function. Disopyramide plus lidocaine and disopyramide plus mexiletine produced increases in the time constant of the fast component of the block (tau f), the fast fraction of the block (Af), and the ratio of the fast to the slow fraction (Af/As). Mexiletine plus flecainide increased tau f, Af, and As; whereas disopyramide plus flecainide caused no changes in the kinetic parameters of use-dependent block. These results suggest that there may be diverse modes of interaction between the drug and the Na+ channel, and the combination of two different types of the drug may sometimes provide different effects on the fast and slow components of the use-dependent block of Vmax.