Article date: August 1999
By: Toshitsugu Ogura, Stephen Jones, Lesya M Shuba, John R McCullough, Terence F McDonald, in Volume 127, Issue 8, pages 1837-1845
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+ (ICa,L) and Ba2+ (IBa,L), concentrations ranging from 0.1 to 100 μM were applied to whole‐cell‐configured guinea‐pig ventricular myocytes.
Although sub‐micromolar concentrations of terodiline had no effect on ICa,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 ICa,L in bladder smooth muscle myocytes.
Terodiline affected ICa,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 ICa,L at 0 mV in a concentration‐dependent manner, and slowed the recovery of channels from inactivation.
Terodiline reduced peak IBa,L more effectively than peak ICa,L, and markedly accelerated the rate of inactivation of the current.
The results are discussed in terms of mechanisms of Ca2+ channel block and relation to the therapeutic and cardiotoxic effects of the drug.
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+ (ICa,L) and Ba2+ (IBa,L), concentrations ranging from 0.1 to 100 μM were applied to whole‐cell‐configured guinea‐pig ventricular myocytes.
Although sub‐micromolar concentrations of terodiline had no effect on ICa,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 ICa,L in bladder smooth muscle myocytes.
Terodiline affected ICa,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 ICa,L at 0 mV in a concentration‐dependent manner, and slowed the recovery of channels from inactivation.
Terodiline reduced peak IBa,L more effectively than peak ICa,L, and markedly accelerated the rate of inactivation of the current.
The results are discussed in terms of mechanisms of Ca2+ channel block and relation to the therapeutic and cardiotoxic effects of the drug.
British Journal of Pharmacology (1999) 127, 1837–1845; doi:10.1038/sj.bjp.0702713
DOI: 10.1038/sj.bjp.0702713
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