The phosphodiesterase III inhibitor olprinone inhibits hippocampal glutamate release via a cGMP/PKG pathway

Olprinone, an inhibitor of cyclic nucleotide phosphodiesterase III, inhibited an increase in intracellular Ca2+ concentrations for acutely dissociated rat hippocampal pyramidal neurons induced by extracellular high K+ (35 mM) depolarization. Olprinone (100 mu M) significantly reduced spontaneous glutamate release from rat hippocampal slices. Furthermore, olprinone significantly decreased the rate of alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (AMPA-mEPSCs) monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was blocked by KT5823, an inhibitor of protein kinase G (PKG), but not by H-89, an inhibitor of protein kinase A (PKA). In the PKA assay using PC-12 cells, olprinone did not activate PKA. Taken together, the results of the present study show that olprinone attenuates intracellular Ca2+ rise through voltage-sensitive Ca2+ channels and inhibits presynaptic glutamate release via a cGMP/PKG pathway. (C) 2008 Elsevier Ireland Ltd. All rights reserved.