LEAD INCREASES INOSITOL 1,4,5-TRISPHOSPHATE LEVELS BUT DOES NOT INTERFERE WITH CALCIUM TRANSIENTS IN PRIMARY RAT ASTROCYTES

Alteration of receptor-mediated signal transduction pathways by inorga nic lead (Pb) has been postulated to contribute to the neurotoxicity o f this environmental toxicant, some of these effects involving astrocy tes. As Pb is known to mimic Ca2+ in various biological systems or alt er Ca2+-mediated cellular processes, we analyzed the effect of Pb expo sure on al receptor activated astrocytic phosphoinositide metabolism a nd Ca2+ responses in primary astrocyte cultures prepared from cerebral cortex of 1-day-old rats. Exposure to norepinephrine (NE; 10-100 muM) resulted in a significant increase in astrocytic inositol 1,4,5-trisp hosphate levels, concomitant with an increase in intracellular Ca2+ le vels. Fifteen minute exposure to Pb (10 muM lead acetate) significantl y increased inositol 1,4,5-trisphosphate generation compared with cont rols, both in the presence and absence of NE. However, the inositol 1, 4,5-trisphosphate-mediated Ca2+ transients following NE stimulation wa s unaltered in the presence of Pb (1-100 muM). NE-evoked intracellular Ca2+ responses, both in the presence and absence of extracellular Ca2 + did not differ between control and Pb-treated astrocytes. Additional studies failed to demonstrate the occurrence of Pb influx into astroc ytes within the first 12 min of exposure such that Ca2+ responses woul d be directly affected. It therefore appears unlikely that astrotoxic effects of Pb are mediated via direct changes in intracellular Ca2+ tr ansients.