NORADRENALINE STIMULATION UNBALANCES THE PHOSPHOINOSITIDE CYCLE IN RAT CEREBRAL CORTICAL SLICES

Muscarinic cholinergic and alpha1-adrenoceptor-mediated stimulation of phosphoinositide hydrolysis in rat cerebral cortex were compared by m easuring carbachol- and noradrenaline-induced accumulation of various intermediates of the phosphoinositide cycle. Unlike carbachol, noradre naline in the presence of guanosine 5'-O-(3-thiotriphosphate) did not stimulate phospholipase C activity in brain cortical membranes. In cor tical slices, the efficacy of noradrenaline to stimulate accumulation of H-3-inositol phosphates and [P-32]phosphatidic acid was 2.5 to thre efold that of carbachol. However, noradrenaline was less effective tha n carbachol in stimulating accumulation of [H-3]CDP-diacylglycerol and resynthesis of phosphatidylinositol. This was not due to calcium inhi bition of CTP:phosphatidate cytidyltransferase or to different lithium requirements for carbachol- and noradrenaline-stimulated accumulation of [H-3]CDP-diacylglycerol. The noradrenaline-induced unbalance of th e phosphoinositide cycle, which was most apparent at relatively high c oncentrations of calcium (2.5 mM) in the incubation buffer, was qualit atively reproduced with ionomycin. The use of the alpha1a-subtype-sele ctive adrenoceptor antagonists WB4101 and 5-methylurapidil revealed a single alpha1a-like component mediating the effects of noradrenaline. Our results suggest that the primary mechanism for phospholipase C act ivation by brain alpha1 adrenoceptors involves an increase in intracel lular calcium concentration.