Effect of CD349, a new dihydropyridine derivative Ca2+ antagonist, on the voltage-dependent Ca2+ currents in isolated mammalian brain neurons.
The effects of CD349 [2-nitratopropyl-3-nitratopropyl-2,6-dimethyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate], a dihydropyridine derivative Ca2+ antagonist, were studied on low and high voltage-activated Ca2+ currents in single pyramidal neurons isolated from the rat hippocampal CA1 region. CD349 inhibited the peak amplitude of the low voltage-activated Ca2+ current in a concentration-dependent manner with a threshold concentration of about 10(-7) M. The concentration for half-maximum inhibition was 1.5 x 10(-6) M. At 10(-5) M or more, a complete suppression of the low voltage-activated Ca2+ current was observed. There was no apparent effect on the current-voltage relationship and the current kinetics (rising and decaying phases of the current). The inhibitory potency of CD349 was similar to that of nicardipine. CD349, at a concentration of 10(-6) M (near the half-maximum inhibition concentration), delayed the reactivation and enhanced voltage- and time-dependently the inactivation of the low voltage-activated Ca2+ channel, suggesting that CD349 preferentially binds to the inactivated Ca2+ channel. CD349 also decreased the peak amplitude of the high voltage-activated Ca2+ current at half-maximum inhibition concentrations of 5.7 x 10(-6) M. The current kinetics of the high voltage-activated Ca2+ current were slightly accelerated without shifting the current-voltage relationship in the presence of 10(-5) M of CD349. The potency of CD349 in inhibiting both types of Ca2+ current was also similar to that of nicardipine. It is suggested that the blocking effect of CD349 on neuronal Ca2+ influx, in combination with a cerebral vasodilatory action, may contribute to a favorable effect on ischemic brain damage.
Oyama
Y
Y
Department of Neurophysiology, Tohoku University School of Medicine, Sendai, Japan.
Nakaye
T
T
Akaike
N
N
Tsuchida
K
K
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C054179:CD 349; D009529:Nicardipine; D002118:Calcium