PHLORETIN AS AN ANTAGONIST OF PROSTAGLANDIN-F2-ALPHA RECEPTOR IN CULTURED RAT ASTROCYTES

The effect of phloretin on prostaglandin (PG) F2alpha-induced phosphoinositide hydrolysis and elevation of intracellular Ca2+ concentration was examined in cultured rat astrocytes. Phloretin inhibited PGFalpha (1 muM)-induced phosphoinositide hydrolysis in a concentration-dependent manner with an IC50 value of 16 muM. The inhibitory action of phloretin was specific for PGs. The addition of increasing concentrations of phloretin caused progressive shifts of the dose-response curves of PGF2alpha to the right. In digitonin-permeabilized astrocytes, phloretin (100 muM) inhibited the stimulation induced by PGF2alpha (1 muM) plus GTPgammaS (50 muM) without affecting that induced by GTP-gammaS alone. PGF2alpha at 1 muM transiently increased astrocytic intracellular Ca2+ concentration in 39% of the cells tested. The response was completely blocked by 100 muM phloretin and the calcium response recovered again after washing out phloretin. These results suggest that phloretin is an antagonist of PGF2alpha receptor linked to phospholipase C in astrocytes.