Lead increases inositol 1,4,5-triphosphate levels but does not interfere with calcium transients in primary rat astrocytes

Alteration of receptor-mediated signal transduction pathways by inorganic lead (Pb) has been postulated to contribute to the neurotoxicity of this environmental toxicant, some of these effects involving astrocytes. As Pb is known to mimic Ca²⁺ in various biological systems or alter Ca²⁺-mediated cellular processes, we analyzed the effect of Pb exposure on α₁ receptor activated astrocytic phosphoinositide metabolism and Ca²⁺ responses in primary astrocyte cultures prepared from cerebral cortex of 1-day-old rats. Exposure to norepinephrine (NE; 10-100 μM) resulted in a significant increase in astrocytic inositol 1,4,5-trisphosphate levels, concomitant with an increase in intracellular Ca²⁺ levels. Fifteen minute exposure to Pb (10 μM lead acetate) significantly increased inositol 1,4,5-trisphosphate generation compared with controls, both in the presence and absence of NE. However, the inositol 1,4,5-trisphosphate-mediated Ca²⁺ transients following NE stimulation was unaltered in the presence of Pb (1-100 μM). 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 astrocytes within the first 12 min of exposure such that Ca²⁺ responses would be directly affected. It therefore appears unlikely that astrotoxic effects of Pb are mediated via direct changes in intracellular Ca²⁺ transients.