The effect of calmodulin inhibitors of the adenylate cyclase system.

Abstract

Experiments using a cytochemical method showed the presence of a specific precipitate of the adenylate cyclase (AC) reaction on the sarcolemma and in the subsarcolemmal cisternae and junctional sarcoplasmic reticulum in rat cardiomyocytes. The localization of AC in the given organelles draws attention to the mutual association between Ca2+ ions and cAMP in the modulation of cardiac contractions. Trifluoperazine (TFP) and chlorpromazine (CHP) are known as phenothiazine derivatives inhibiting cellular enzymatic processes dependent on calmodulin and Ca2+. AC is one of these enzyme systems. The administration of TFP and CHP (both in a dose of 0.1 and 3 mmol.1(-1)) did not affect the cytochemical localization of the enzyme. Quantitative determination of 125I-cAMP by RIA showed that CHP inhibited AC activity in both concentrations. TFP, on the other hand, did not inhibit AC activity in 0.1 mmol.1(-1) concentration and actually stimulated its activation in 3 mmol.1(-1) concentration. The different action of the phenothiazine derivatives on AC activity can be attributed partly to the different affinity of TFP and CHP for calmodulin and partly to interaction of the inhibitor-calmodulin complex with the phosphodiesterase (PDE) system.