Selective block of transient Ca channel current in mouse neuroblastoma cells by U-88779E

HK Im, WB Im and K Tsuzuki

Upjohn Company, CNS Disease Research, Kalamazoo, Michigan.

Antioxidants and T-type Ca channel antagonists are neuroprotective during ischemia or other central nervous system traumas. U-88779E (1- [(4-chlorophenyl-phenyl)-methyl]-4-[(7-methoxy-5-isopropyl- 2,4,6- cycloheptatrien-1-one)-2-methyl]piperazine) has been shown to have both antioxidant activity and the ability to block Ca fluxes in cardiac microsomes. In this study, we examined the effect of U-88779E on Ca, Na and K channels in a neuronal cell line, N1E-115 cells. The drug blocked transient barium current (IBa) through low-threshold Ca channels (T- type) with little effect on other noninactivating IBa including the nifedipine-sensitive one. The drug at 20 microM reduced transient IBa at a constant rate, -7.2% of the control per min, and abolished the current within 15 min. This implies a continuous accumulation of the drug in cell membranes probably because of its high lipophilicity (log P = 7.003). U-88779E also blocked Na and K currents but at a rate about 8 times slower than that observed with transient IBa. Further studies on interactions of the drug with T-channels revealed that the drug had no effect on the shape of current-voltage curve, activation and inactivation kinetics, and steady-state activation curve. The drug, however, induced a hyperpolarizing shift in steady-state inactivation curve and became more potent under conditions where the channels in inactivated states prevail. These observations are consistent with the view that U-88779E has a higher affinity to T-type channels in inactivated states than in resting or open states.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 265, Issue 2, pp. 529-535, 05/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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