Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells.
1. The effect of trimebutine on the voltage-dependent inward Ca2+ current was investigated by the whole-cell voltage-clamp technique in single smooth muscle cells from rabbit ileum. 2. Trimebutine (3-100 microM) reduced the Ca2+ current in a concentration-dependent manner. The inhibitory effect on the Ca2+ current was also dependent on the holding potential. The Ca2+ current after a low holding potential was inhibited to a greater extent than that after a high membrane potential: the IC50 values were 7 microM and 36 microM at holding potentials of -40 mV and -60 mV, respectively. The Ca2+ current elicited from a holding potential of -80 mV could not be reduced by as much as 50% of the control by trimebutine at concentrations as high as 100 microM. 3. Trimebutine (30 microM) shifted the voltage-dependent inactivation curve for the Ca2+ current by 18 mV in the negative direction. The affinity of the drug for Ca2+ channels was calculated to be 36 times higher in the inactivated state than in the closed-available state. 4. Blockade of the Ca2+ current by trimebutine, unlike verapamil, was not use-dependent. 5. The results suggest that trimebutine inhibits the voltage-dependent inward Ca2+ current through a preferential binding to Ca2+ channels in the inactivated state in the smooth muscle cell from rabbit ileum. The inhibitory effect of trimebutine on gastrointestinal motility is discussed in the light of the present findings.
Nagasaki
M
M
Department of Veterinary Science, Faculty of Agriculture, Gifu University, Japan.
Komori
S
S
Ohashi
H
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004594:Electrophysiology; D007082:Ileum / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D014287:Trimebutine / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D014700:Verapamil; D014287:Trimebutine