Selective inhibition of thapsigargin-induced contraction and capacitative calcium entry in mouse anococcygeus by trifluoromethylphenylimidazole (TRIM).
This study examined the effects of trifluoromethylphenylimidazole (TRIM) on tone, and calcium entry, in mouse anococcygeus stimulated by either thapsigargin (Tg; 100 nM) which activates capacitative calcium entry (CCE), or high K (60 mM) which activates voltage-operated calcium channels. TRIM (1 - 333 microM) produced concentration-related relaxation of Tg-induced tone (EC(50), 42 microM) but was much less effective against high K. In single smooth muscle cells loaded with FURA-2, TRIM reduced the increase in fluorescence ratio produced by Tg but had no effect on that produced by high K. The relaxations of Tg-induced tone, and reduction in fluorescence ratio, were obtained in the presence of L-N(G)-nitroarginine and were thus independent of nitric oxide synthase inhibition; further, TRIM had no discernible effect on nitrergic responses. TRIM provides a novel drug for the selective inhibition of CCE and a template for the development of more potent inhibitors.
Gibson
A
A
Centre for Cardiovascular Biology & Medicine, School of Biomedical Sciences, King's College London, Hodgkin Building, Guys Campus, London SE1 9RT. alan.gibson@kcl.ac.uk
Fernandes
F
F
Wallace
P
P
McFadzean
I
I
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019335:Nitroarginine; C098186:1-(2-trifluoromethylphenyl)imidazole; D019284:Thapsigargin; D019001:Nitric Oxide Synthase; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D011188:Potassium; D002118:Calcium