Dihydropyridine calcium channel activators and antagonists influence depolarization-evoked inositol phospholipid hydrolysis in brain.
Increased inositol phospholipid hydrolysis induced by elevated extracellular K+ was directly monitored by assaying [3H]inositol phosphate accumulation following prelabelling of cerebral cortical slices with [3H]inositol. Depolarization evoked by K+ increased [3H]inositol phosphate accumulation with a 2-3-fold stimulation observed at 18 mM K+. Higher concentrations of K+ failed to further increase accumulation though a suppression of the incorporation of [3H]inositol into phospholipid at higher K+ could complicate these results. Slices incubated with the dihydropyridine calcium channel activator BAY-K-8644 resulted in a much increased response to 12 mM and 18 mM K+ with substantially smaller enhancement of basal (6 mM) or much higher (30 and 55 mM) K+. The [3H]inositol phosphate response induced by 18 mM K+ + 1 microM BAY-K-8644 was markedly reduced when incubations were performed in the presence of reduced Ca2+. Similarly, preincubation of slices with the dihydropyridine antagonist PN-200-110 suppressed the response to K+ and to K+ + BAY-K-8644. This effect was stereospecific with the (+)-enantiomer being at least 100-fold more potent than the (-)-enantiomer. These data provide primary evidence for functional dihydropyridine-sensitive calcium channels in brain.
Kendall
D A
DA
Nahorski
S R
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013403:Sugar Phosphates / Q000378:metabolism*
D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D007473:Ion Channels; D011725:Pyridines; D013403:Sugar Phosphates; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D011188:Potassium