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Molecular Pharmacology, Vol 16, 841-850, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Depolarization-Induced Inhibition of Cyclic AMP Accumulation: Cholinergic-Adrenergic Antagonism in Murine Atria

JOAN HELLER BROWN 1

1 Division of Pharmacology, Department of Medicine, M-013, University of California, San Diego, La Jolla, California 92093

Isolated mouse heart atria incubated in medium containing 57 mM potassium chloride (K+) lose their capacity to make cyclic AMP when stimulated with isoproterenol. With lower concentrations of medium K+ (22 and 40 mM) there is partial blockade of catecholamine sensitive cyclic AMP accumulation. Inhibition is apparent within minutes of exposure to high K+ medium and is reversed in atria returned to medium of normal (6 mM) K+ concentration. K+ induced inhibition requires external calcium, and is blocked by atropine. The cholinergic, agonist, carbachol, also blocks isoproterenol-responsive cyclic AMP accumulation in murine atria, with an IC50, of 0.1 µM. Inhibition by carbachol is reversed by atropine, but in contrast to the effect of K+, carbachol-induced inhibition does not require external calcium. Both K+ and carbachol produce noncompetitive inhibition of isoproterenol stimulated cyclic AMP accumulation, with 85-90% inhibition at maximal concentrations. Neither manipulation lowers the basal cyclic AMP concentration or the increase in cyclic AMP produced by cholera toxin. Catecholamine-sensitive cyclic AMP accumulation is also markedly depressed in atria incubated with the cholinesterase inhibitor, physostigmine, and in atria exposed to millimolar concentrations of choline (to replace sodium). Atropine abolishes the inhibition produced by these interventions. The findings presented here demonstrate muscarinic antagonism of isoproterenol-sensitive cyclic AMP accumulation in murine atria and suggest that acetylcholine released from cholinergic nerve endings by K+ depolarization or released spontaneously while cholinesterase is inhibited, can regulate cyclic AMP responses to adrenergic stimulation. The marked noncompetitive inhibition of atrial cyclic AMP accumulation by locally released acetylcholine may be basic to parasympathetic antagonism of sympathetic responses in the myocardium.

Note:
ACKNOWLEDGMENT The technical assistance of Mr. Michael Branks is gratefully acknowledged. This work would not have been possible without the support and encouragement of Dr. Steven E. Mayer.

Submitted on March 19, 1979
Accepted on June 5, 1979




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[Abstract] [Full Text] [PDF]


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