Effects of the Class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes

Abstract

The methanesulphonanilide agent dofetilide (UK-68,798) exerts Class III antiarrhythmic effects by inhibiting the cardiac rapid delayed rectifier potassium current (I(Kr)) encoded by HERG. The aim of the present study was to determine whether dofetilide also exhibits Class IV (L-type calcium-channel blocking) effects. L-type calcium current (I(Ca,L)) was measured from rabbit isolated ventricular myocytes, using the whole-cell patch-clamp technique under selective recording conditions. Positive control experiments demonstrated inhibition of I(Ca,L) elicited by pulses to + 10 mV by both nifedipine and externally applied Ni2+ ions. Three concentrations of dofetilide were tested: 100 nM, 1 microM and 10 microM. I(Ca,L) magnitude was not significantly reduced by any of the concentrations tested (P > 0.05; n = minimum of seven cells per drug concentration). The inactivation time-course of I(Ca,L) was also unaffected by 10 microM dofetilide. Heterologously expressed HERG current (I(HERG)) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 microM dofetilide, with inhibition at 1 microM not significantly different from 100% (P > 0.1). It is concluded that dofetilide produced no I(Ca,L) blocking effects at concentrations up to and exceeding that required for maximal I(HERG) inhibition. The findings support the notion that dofetilide is a highly selective Class III antiarrhythmic agent, devoid of Class IV antiarrhythmic activity.

Dofetilide Enhances the Contractility of Rat Ventricular Myocytes via Augmentation of Na+–Ca2+ Exchange

“…When stimulated by the I Ca elicit waveform, the Ca 2+ transient was triggered and cell contraction was provoked by elevating intracellular Ca 2+ . DOF 0.2 μM had no influence on I Ca in this experiment, which is consistent with the studies by Paul et al [37], but remarkably increased intracellular Ca 2+ transient and cell shortening. These results strongly suggest that DOF enhances contraction by a mechanism other than affecting the I Ca .…”

Paradoxical Effect of Dofetilide on Action Potential Duration and Calcium Transient Amplitude in Newborn Rabbit Ventricular Myocytes

“…Nonetheless the role of I Ca in neonates cannot be neglected. The 15%-25% decrease in peak I Ca observed in response to dofetilide, an effect not demonstrated in adult rabbit myocytes, 8 likely contributes to the decrease in calcium transient amplitude that we observed in voltage clamped cells.…”

“…In adult cells, dofetilide (0.1, 1, and 10 mM) increased APD, but despite the increase in APD, there is reportedly no change in calcium current. 8 With the shortening of APD electrophysiologically in adults, we observed a decrease in the amplitude of the calcium transients (Fig. 2), but no change was observed when APD was prolonged pharmacologically using dofetilide (Figs.…”

“…7 A study by Paul et al shows that dofetilide (0.1, 1.0, and 10 mM) does not inhibit L-type calcium current (I Ca ) in adult rabbit ventricular myocytes. 8 Thus, dofetilide is reportedly a selective class III agent, without class IV (calcium channel-blocking) activity. Experimental animal studies indicate that the immature mammalian myocardium is more sensitive to the APD-prolonging effects of I Kr blockers than the adult.…”

Cardiac Ion Channel Effects of Tolterodine

“…Tolterodine had little effect on voltagedependent Na ϩ channels even at concentrations up to 1 M. We believe the data support the notion that tolterodine is a potent mixed ion channel antagonist in the heart with prominent effects on both HERG and the L-type Ca 2ϩ channel. In contrast, dofetilide is known to be a specific inhibitor of HERG/I Kr with no effects on Ca 2ϩ channels up to 10 M (Paul et al, 2001). A head-to-head comparison of these two drugs on action potential waveforms revealed that tolterodine produced far less APD prolongation relative to dofetilide.…”