Molecular Pharmacology, Vol 10, 941-953, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Egress of Adenosine 3', 5'-Monophosphate from Pigeon Erythrocytes

¹ Division of Pharmacology, Department of Medicine, University of California, San Diego, La Jolla, California 92037

The formation of adenosine 3',5'-monophosphate (cyclic AMP) is a response of nucleated pigeon erythrocytes that appears to be specific to catecholamines and is associated with the rapid appearance of the nucleotide in the incubation medium. Norepinephrine, 10 µM, produced a maximal response in 30-60 min of about 1 nmole of cyclic AMP accumulating both inside and outside cells when 25 µl of packed erythrocytes were incubated in 2 ml of buffered 0.154 M NaCl at 37°. The extrusion of cyclic AMP was primarily unidirectional and was inhibited by iodoacetate, prolonged incubation, and a high concentration of cyclic AMP in the medium. Extrusion was also inhibited by certain drugs. Notably potent was vinblastine (0.3 µM), which did not affect norepinephrine-induced intracellular accumulation of cyclic AMP. Colchicine (300 µM) and papaverine (100 µM) inhibited extrusion. These drugs also caused augmentation of intracellular cyclic AMP, probably as a result of inhibition of red cell cyclic nucleotide phosphodiesterase. Griseofulvin (300 µM) inhibited extrusion while partly reducing the norepinephrine-induced accumulation of intracellular cyclic AMP. Other agents which inhibited extrusion were quinine, quinidine, phenol red, chloroform, and toluene. Since most of the agents tested have been shown to bind microtubule protein or inhibit mitosis at metaphase, it is suggested that cyclic AMP extrusion from nucleated avian erythrocytes depends upon the integrity of microtubules or of analogous components in the plasma membrane. However, observations such as inhibition of extrusion by vinblastine without enhancement of intracellular accumulation of cyclic AMP indicate that drugs which affect extrusion may influence other related processes—cyclic AMP synthesis of degradation—and that alteration of one of these processes in turn influences the others.

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