INHIBITION BY VERATRIDINE OF CARBACHOL-STIMULATED INOSITOL TETRAKISPHOSPHATE ACCUMULATION IN RAT-BRAIN CORTICAL SLICES

The present studies examined the inhibitory effect of veratridine (a N a+ channel activator) on carbachol (a cholinergic agonist) stimulated inositol 1,3,4,5-tetrakisphosphate accumulation in rat brain cortical slices. Veratridine inhibited carbachol stimulation of inositol 1,3,4, 5-tetrakisphosphate formation (after a delay of about 30 seconds) at 6 0 or 120 seconds when there was little inhibition of inositol 1,4,5 tr isphophate accumulation. The inhibitory effect of veratridine on carba chol stimulated inositol 1,3,4,5-tetrakisphosphate accumulation was ab olished in the presence of ouabain or tetrodotoxin but was unaffected in low calcium conditions. Veratridine reduced the total ATP content a nd this effect was abolished by tetrodotoxin. The inhibitory effect of 10 but not 30 mu M veratridine on inositol 1,3,4,5-tetrakisphosphate accumulation in the presence of carbachol was reversed by the presence of exogenous 8-bromo cyclic AMP or forskolin which activates adenylyl cyclase. However, the decrease in brain slice ATP seen in the presenc e of veratridine was unaffected by forskolin. Our results are compatib le with the hypothesis that veratridine inhibition of carbachol-stimul ated inositol 1,3,4,5-tetrakisphosphate formation is due to depletion of ATP at the site of Ins 1,3,4,5-P-4 formation from Ins 1,4,5-P-3.