Molecular Pharmacology, Vol 10, 615-625, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Selective Alteration of the Activity of the Multiple Forms of Adenosine 3', 5'-Monophosphate Phosphodiesterase of Rat Cerebrum

¹ Department of Pharmacology, Medical College of Pennsylvania, Philadelphia, Pennsylvania 19129, and Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeths Hospital, Washington, D. C. 20032

Four different peaks of cyclic 3',5'-AMP phosphodiesterase activity were isolated from the supernatant fraction of rat cerebral homogenates using preparative acrylamide gel electrophoresis. These peaks of activity, designated I-IV according to the order in which they emerged from the column, were exposed to various inhibitors of phosphodiesterase and to an activator of phosphodiesterase isolated from brain. The activator stimulated peak II phosphodiesterase about 10-fold but had no effect on the other peaks. The inhibitors also had differential effects on the phosphodiesterases, the most notable being trifluoperazine, which preferentially inhibited the activated peak II. Trifluoperazine sulfoxide and promethazine had less than 10% of the inhibitory activity of trifluoperazine on peak II. The inhibitors differed not only in the specific phosphodiesterase which they inhibited but also in their mechanism of action. Thus theophylline, cyclic GMP, and low concentrations of papaverine acted as competitive inhibitors, whereas the inhibition produced by trifluoperazine was neither purely competitive nor purely noncompetitive. High concentrations of papaverine produced noncompetitive inhibition. Theophylline and papaverine inhibited the activated and unactivated peak II equally, but trifluoperazine inhibited the activated peak II by more than 90% in concentrations (40 µM) that had little effect on the unactivated enzyme. This inhibition of peak II phosphodiesterase by trifluoperazine could be prevented by increasing the concentration of activator. Our results suggest that the selectivity of phosphodiesterase inhibitors may be due to the different patterns and ratios of multiple forms of phosphodiesterase in different tissues.

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ACKNOWLEDGMENT We thank Ms. Kathleen Callison for her excellent technical assistance.