THE EFFECT OF DIHYDROPYRAZOLES ON RELEASE OF [H-3] GABA FROM NERVE-TERMINALS ISOLATED FROM MAMMALIAN CEREBRAL-CORTEX

Two dihydropyrazoles (RH 3421 and RH 5529) were examined for their effects on release of [3H]GABA from superfused synaptosomes isolated from guinea pig central nervous system. Both compounds reduced the spontaneous release of [3H]GABA from resting synaptosomes. RH 3421 and RH 5529 inhibited veratridine-induced release of neurotransmitter at low concentrations and in a dose-dependent manner. The inhibitory potency was greater for RH 3421 (IC50 = 40 nM) than RH 5529 (IC50 = 450 nM). In addition, both dihydropyrazoles markedly decreased the release of [3H]GABA evoked by the α-cyanopyrethroid deltamethrin and scorption (Leiurus quinquestriatus) venom. At 10 μM, RH 3421 failed to influence 25 mM potassium-induced release of [3H]GABA, although significant inhibitory effects were observed with RH 5529 at this concentration. Our results demonstrate that presynaptic sites sensitive to the action of dihydropyrazoles exist in mammalian central nervous system. RH 3421 and RH 5529, like tetrodotoxin, are potent inhibitors of both spontaneous release of neurotransmitter and the transmitter releasing effects of sodium channel activators in guinea pig cortex. RH 3421 is highly selective in this respect while RH 5529 is less specific and at high concentrations perturbs an additional mechanism involved in transmitter secretion. © 1990.