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 c lass III antiarrhythmic effect of dofetilide. Action-potential duratio n (APD) was determined in guinea pig papillary muscle by microelectrod e techniques at different stimulation frequencies (0.5-3 Hz). The APD- prolonging effect (Delta APD) of 10 nM dofetilide was reversed frequen cy dependent; it was 51 +/- 6 ms at 0.5 Hz and lower at 3 Hz, 21 +/- 3 ms. Either 10 mu M diltiazem or 0.1 mu M Bay K 8644 (BayK) was added to decrease or increase L-type calcium currents. In the presence of do fetilide + diltiazem, Delta APD was reduced to 32 +/- 4 ms at 0.5 Hz b ut not affected at 3 Hz. Conversely, dofetilide + BayK further prolong ed Delta APD to 78 +/- 10 ms at 0.5 Hz but not at 3 Hz. When 10 mu M d ihydroouabain, a digitalis glucoside, was added to dofetilide, Delta A PD 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 m odulated by altering L-type calcium currents. With reduced calcium cur rent, the frequency profile is less reversed and more favorable. The s imilarity of BayK and dihydroouabain in aggravating the reversed frequ ency-dependent effect of dofetilide is in Line with a contribution of intracellular calcium to this reversed rate-dependent profile in the g uinea pig ventricle.