SK-AND-F96365 ]-4-METHOXYPHENYLETHYL)-1H-IMIDAZOLEHYDROCHLORIDE) STIMULATES PHOSPHOINOSITIDE HYDROLYSIS IN HUMAN U373 MG ASTROCYTOMA-CELLS

SK&F 96365 phenyl)propoxy]-4-methoxyphenylethyl}-1H-imidazole hydrochl oride) stimulated the accumulation of [H-3]inositol monophosphates ([( 3H)]IP1) in human U373 MG astrocytoma cells prelabelled with [H-3]inos itol (EC50 15 +/-1 mu M, Hill coefficient 3.8 +/- 0.4). SK&F 96365-ind uced accumulation of [H-3]IP1 increased linearly with time, but there was no initial rapid formation of [H-3]IP1. SK&F 96365 also stimulated [H-3]IP1 accumulation in human HeLa cells, but only to a small extent in slices of rat cerebral cortex and guinea-pig cerebellum. SK&F 9636 5-induced accumulation of [H-3]IP1 in U373 MG cells increased as extra cellular Ca2+ was increased from nominally zero to 4 mM, but there was no evidence that SK&F 96365 induced any marked entry of Ca2+ into cel ls; only an inhibition of store-refilling-induced Ca2+ entry was appar ent. Further, the response to SK&F 96365 was additive with that to the Ca2+ ionophore ionomycin. Depolarization of the cells with raised Kproduced only a small stimulation of phosphoinositide hydrolysis. SK&F 96365 caused the release of Ca2+ from intracellular stores in U373 MG cells (EC50 26 +/- 14 mu M), but thapsigargin induced only a small ac cumulation of [H-3]IP1. Miconazole, another N-substituted imidazole, a lso stimulated [H-3]IP1 accumulation in U373 cells. (C) 1998 Elsevier Science Inc.