Frequency dependence in the action of the class III antiarrhythmic drug dofetilide is modulated by altering L-type calcium current and digitalis glucoside.

We investigated how modulation of L-type calcium current affects the class II antiarrhythmic effect of dofetilide. Action-potential duration (APD) was determined in guinea pig papillary muscle by microelectrode techniques at different stimulation frequencies (0.5-3 Hz). The APD-prolonging effect (deltaAPD) of 10 nM dofetilide was reversed frequency dependent; it was 51 +/- 6 ms at 0.5 Hz and lower at 3 Hz, 21 +/- 3 ms. Either 10 microM diltiazem or 0.1 microM Bay K 8644 (BayK) was added to decrease or increase L-type calcium currents. In the presence of dofetilide + diltiazem, deltaAPD was reduced to 32 +/- 4 ms at 0.5 Hz but not affected at 3 Hz. Conversely, dofetilide + BayK further prolonged deltaAPD to 78 +/- 10 ms at 0.5 Hz but not at 3 Hz. When 10 microM dihydroouabain, a digitalis glucoside, was added to dofetilide, deltaAPD was more pronounced at 0.5 Hz and reduced at 3 Hz. We conclude that the reversed frequency-dependent effect of dofetilide on APD can be modulated by altering L-type calcium currents. With reduced calcium current, the frequency profile is less reversed and more favorable. The similarity of BayK and dihydroouabain in aggravating the reversed frequency-dependent effect of dofetilide is in line with a contribution of intracellular calcium to this reversed rate-dependent profile in the guinea pig ventricle.