A selective blocker for rested T-type Ca++ channels in guinea pig atrial cells.
The T-type Ca++ channel is widely distributed. Its physiological roles have not been well established because of the lack of a selective T-channel blocker. By using the suction pipette method, the authors describe (7-[[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]methyl]-2-[(2- hydroxyethyl)amino]4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one) or U-92032, which selectively blocks rested closed T-type Ca++ channels (T channel). After a 3-min exposure to external U-92032 (1 microM), a 50% resting block of the T channel was observed on the first step depolarization from -90 to -40 mV; subsequent stimulations at 0.1 Hz produced little further block. The L-type Ca++ current (L channel) was not affected. At 10 microM, U-92032 produced about 100% resting block of the T and 20% block of the L channels. Subsequent stimulations at 0.1 Hz increased the block of L channel to 56% at the sixth pulse, which indicated strong use dependence at negative potentials and low stimulation rates. Blockade of the T channel did not alter channel steady-state activation and inactivation or current inactivation time courses. By contrast, blockade of the L channel shifted the midpoint of its steady-state inactivation curve from -20.6 mV to -27.8 mV and accelerated its slow inactivation time course, from 171 +/- 16 msec to 79.8 +/- 9.3 msec. Moreover, the 90% recovery time from inactivation was increased from 0.12 to 60 sec. Because U-92032 is ionized at pH 7, its inability to affect the T channel gating property may suggest external drug binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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Upjohn Laboratories, Kalamazoo, Michigan.
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D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D010879:Piperazines; C086422:U 92032; D014334:Tropolone