Selective inhibition of T-type Ca2+ channels by Ro 40-5967.
The present study shows that the chemically novel nondihydropyridine Ca2+ antagonist, Ro 40-5967, blocks T-type divalent ion currents in vascular muscle cells. T-type Ca2+ channels were blocked selectively and completely by therapeutic concentrations of 1 to 10 mumol/L Ro 40-5967, at which there was only 25% to 70% block of L-type Ca2+ currents. Using the combination of Ro 40-5967 and nisoldipine, a dihydropyridine selective for L-type Ca2+ channels, we found that all Ca2+ current could be completely blocked; thus, Ro 40-5967 is the first Ca2+ channel blocker to eliminate dihydropyridine-insensitive voltage-dependent Ca2+ current at therapeutically useful concentrations. The stepwise sequential block of T- and L-type Ca2+ currents demonstrated in the present study fulfills the functional criterion for the separate identity of the two Ca2+ channel types, and introduces a pharmacological tool that promises to be important in the exploration of T-type Ca2+ channel function.
Mishra
S K
SK
Oregon Regional Primate Research Center, Beaverton 97006.
Hermsmeyer
K
K
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004338:Drug Combinations; D004594:Electrophysiology; D020748:Mibefradil; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015737:Nisoldipine / Q000494:pharmacology; D009994:Osmolar Concentration; D051381:Rats; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004338:Drug Combinations; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D015737:Nisoldipine