The mechanism of modification by propranolol of the metabolism of phosphatidyl-CMP (CDP-diacylglycerol) and other lipids in the rat pineal gland

Abstract

The mechanism underlying the alteration of phospholipid metabolism in rat pineal gland in vitro produced by propranolol and tertiary amine local anesthetics was investigated. 0.1 mM propranolol did not affect either the levels or specific activity of [32P]ATP in glands. In the presence of the drug, the incorporation of cytidine, but not of inorganic phosphate, into phosphatidyl-CMP (CDP-diacylglycerol) was dependent on the cytidine concentration. The incorporation of glycerol into phosphatidyl-CMP, phosphatidylinositol and phosphatidylglycerol was enhanced by propranolol, whereas labeling of phosphatidylcholine was decreased. When both 1 mM propranolol and 1 mM inositol were present, labeling of phosphatidylinositol was further increased, stimulation of phosphatidyl-CMP and phosphatidylglycerol labeling was reduced and incorporation into phosphatidylcholine and triacylglycerol was depressed. The incorporation of [3H]inositol into pineal lipids was also enhanced by propranolol. 10 microM propranolol inhibited rat liver phosphatidic acid phosphohydrolase by 50%, while local anesthetics were less potent in the decreasing order: dibucaine greater than tetracaine greater than lidocaine greater than procaine. The propranolol-induced accumulation of phosphatidyl-CMP was prevented by supplying adequate freely diffusible inositol in the medium. The phosphatidyl-CMP which accumulated was not utilized for the enhanced formation of phosphatidylinositol brought about by norepinephrine. The results indicate that propranolol and local anesthetics redirect pineal phospholipid metabolism in part by inhibition of phosphatidic acid phosphohydrolase.