Effect of KB-2796, a new diphenylpiperazine Ca2+ antagonist, on voltage-dependent Ca2+ currents and oxidative metabolism in dissociated mammalian CNS neurons.
The effects of KB-2796, 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4- trimethoxybenzyl)piperazine-2HCl, on the low- and high-voltage activated Ca2+ currents (LVA and HVA ICa, respectively) and on oxidative metabolism were studied in neurons freshly dissociated from rat brain. KB-2796 reduced the peak amplitude of LVA ICa in a concentration-dependent manner with a threshold concentration of 10(-7) M when the LVA ICa was elicited every 30 s in the external solution with 10 mM Ca2+. The concentration for half-maximum inhibition (IC50) was 1.9 x 10(-6) M. At 10(-5) M or more of KB-2796, a complete suppression of the LVA ICa was observed in the majority of neurons tested. There was no apparent effect on the current-voltage (I-V) relationship and the current kinetics. KB-2796 delayed the reactivation and enhanced the inactivation of the Ca2+ channel for LVA ICa voltage- and time-dependently, suggesting that KB-2796 preferentially binds to the inactivated Ca2+ channel. KB-2796 at a concentration of 3.0 x 10(-6) M also decreased the peak amplitude of the HVA ICa without shifting the I-V relationship. In addition, KB-2796 reduced the oxidative metabolism (the formation of reactive oxygen species) of the neuron in a concentration-dependent manner with a threshold concentration of 3 x 10(-6) M. It is suggested that the inhibitory action of KB-2796 on the neuronal Ca2+ influx and the oxidative metabolism, in combination with a cerebral vasodilatory action, may reduce ischemic brain damage.
Department of Neurophysiology, Tohoku University School of Medicine, Sendai, Japan.
N
N
Akaike
H
H
Ishibashi
H
H
Hara
Y
Y
Oyama
T
T
Ueha
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002531:Cerebellum / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D005434:Flow Cytometry; D005444:Flunarizine / Q000494:pharmacology; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009761:Nystatin / Q000494:pharmacology; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D011712:Pyramidal Tracts / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005452:Fluoresceins; D005456:Fluorescent Dyes; D010879:Piperazines; D009761:Nystatin; C037631:2',7'-dichlorofluorescein; C052424:lomerizine; D005444:Flunarizine