Block and modified gating of cardiac calcium channel currents by terodiline

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