Intrauterine hypoxia-ischemia reduces phosphoinositide hydrolysis stimulated by metabotropic glutamate receptor agonists in cultured rat cerebellar granule cells.

Effects of intrauterine hypoxia-ischemia (HI) on receptor-stimulated phosphoinositide (PPI) hydrolysis were studied in rat cerebellar granule cell cultures prepared from an in utero HI model. On gestation day 17, HI conditions were achieved by complete clamping of the uterine vasculature for 30 min followed by removal of the clamps to permit reperfusion. Sham operation (SH, surgery without vasculature ligation) was performed as the control. Intrauterine HI did not affect the basal level of PPI hydrolysis (in the absence of stimulants) in cells prepared from either the SH or the HI group. PPI hydrolysis stimulated by quisqualate (QA) or trans-(1S,3R)-1-amino-1,3-cyclo-pentanedicarboxylic acid (trans-ACPD) was significantly reduced in cells prepared from the HI group, whereas intrauterine HI did not affect the PPI hydrolysis induced by ionotropic glutamate receptor agonists or by norepinephrine or serotonin. At a dose range of 100-300 microM, QA-stimulated PPI hydrolysis in cells prepared from the SH group increased by 3-to 4.5-fold, while this increase was only 2- to 2.5-fold in cells prepared from the HI group. Presence of L-NG-monomethyl-arginine (L-NMMA), a nitric oxide (NO) synthase inhibitor, did not increase QA-stimulated PPI hydrolysis in cells prepared from either the SH or the HI group, indicating that stimulation of NO formation is unlikely involved in the suppressive effects of intrauterine HI on QA-induced PPI hydrolysis. The QA-stimulated PPI hydrolysis in cells prepared from the HI group, but not from the SH group, was further inhibited by L-(+)-2-amino-3-phosphono-propionic acid (L-AP3). The overall results suggest that intrauterine HI has long-lasting suppressive effects on metabotropic glutamate receptor agonist-stimulated PPI hydrolysis and these effects might be associated with alterations in expression of metabotropic glutamate receptor subtypes.