Block and modified gating of cardiac calcium channel currents by terodiline

1. Terodiline, an anticholinergic/antispasmodic drug effective in the treatment of urinary incontinence, is presently restricted due to adverse side effects on cardiac function. To characterize its effects on cardiac L-type Ca²⁺-channel current carried by Ca²⁺ (I(Ca,L)) and Ba²⁺ (I(Ba,L)), concentrations ranging from 0.1 to 100 μM were applied to whole-cell-configured guinea-pig ventricular myocytes. 2. Although sub-micromolar concentrations of terodiline had no effect on I(Ca,L) at 0 mV, 100 μM drug reduced its amplitude to ca. 10% of pre-drug control. The estimated IC₅₀ (15.2 μM in K-dialysed cells. 12.2 μM in Cs⁺-dialysed cells; 0.1 Hz pulsing rate) is eight times higher than reported for I(Ca,L) in bladder smooth muscle myocytes. 3. Terodiline affected I(Ca,L) in a use-dependent manner; block increased when the pulsing rate was increased from 0.1 to 2-3 Hz, and when holding potential was lowered from -43 mV. The drug accelerated the decay of I(Ca,L) at 0 mV in a concentration-dependent manner, and slowed the recovery of channels from inactivation. 4. Terodiline reduced peak I(Ba,L), more effectively than peak I(Ca,L), and markedly accelerated the rate of inactivation of the current. 5. The results are discussed in terms of mechanisms of Ca²⁺ channel block and relation to the therapeutic and cardiotoxic effects of the drug.