Vol. 105, No. 3, 1982 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS April 14, 1982 Pages 1142-1149 INTERACTION OF CALCIUM ANTAGONISTS WITH CYCLIC AMP PHOSPHODIESTERASES AND CALMODULIN Paul M. Epstein, Karen Fiss, Reiko Hachisu, and David M. Andrenyak Department of Pharmacology University of Connecticut Health Center Farmington, Connecticut 06032 Received March 5, 1982 The calcium antagonists, nimodipine and nicardipine, competitively inhibited calmodulin-sensitive and calmodulin-insensitive forms of cyclic AMP phosphodiesterase, with IC501s in the micromolar range. Verapamil showed similar inhibitory potency against calmodulin-insensitive phosphodiesterases, but in marked contrast, it was a very weak inhibitor (30-100 times less potent) against calmodulin-sensitive forms of the enzyme. Verapamil and nimodipine both antagonized the calmodulin stimulation of phosphodiestRrase. Through use of hydrophobic fluorescent probes, verapamil, and another calmodulin antagonist, proadifen, were shown to interact directly with calmodulin in a manner that differed from the interaction of calmodulin with trifluoperazine. INTRODUCTION The 1, 4-dihydropyridine derivatives, nimodipine (1) and nicardipine (21, and the papavarine derivative, verapamil (31, have all been shown to belong to a class of drugs termed calcium antagonists by virtue of their ability to block the slow calcium channel in the sarcolemma of cardiac and smooth muscles (4,5). The ability of these compounds to block slow calcium channels, and their associated vasodilatory properties, suggest great promise for their use in several different types of cardiovascular disease, including the management of angina, particulary that caused by coronary vasospasm (6, 7). Since both calmodulin and cyclic AMP play critical regulatory roles in the control of smooth muscle contraction and relaxation (81, and since all the possible mechanisms by which calcium antagonists could work have not yet been fully explored, we have examined the effects of calcium antagonists as inhibitors of cyclic AMP phosphodiesterases and as antagonists of calmod- ulin. We find that these drugs represent a class of potent inhibitors of some forms of phosphodiesterase and that they can antagonize the calmodulin stimulation of phosphodiesterase. These studies also suggest that verapamil may be a useful tool for selective inhibition of calmodulin insensitive phosphodiesterases. 0006-291X/82/071142-08$01.00/0 Copyright 0 1982 by Academc Press, Inc. A II rlghts of reproduction in any form reserved. 1142