Molecular Pharmacology, Vol 20, 113-117, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Calcium-Dependent Blockade of Cardiac Cyclic AMP Accumulation by Batrachotoxin and Veratridine

¹ Division of Pharmacology, Department of Medicine M-103, University of California San Diego, La Jolla, California 92093

Batrachotoxin and veratridine are cardiotoxic alkaloids that cause a persistent activation of the fast sodium channel of excitable cells. Murine cardiac atria exposed to these toxins in vitro lose the capacity to accumulate cyclic AMP in response to isoproterenol. This effect is seen at concentrations of toxin comparable to those necessary to increase sodium permeability in other systems (10-100 nM for batrachotoxin; 20-100 µM for veratridine) and is antagonized by the specific sodium channel blocking agent, tetrodotoxin. Extracellular calcium is required for inhibition of the cyclic AMP response by batrachotoxin and veratridine. Atria exposed to these agents also undergo a marked loss of intracellular ATP and there is a concomitant decrease in GTP content. ATP depletion is also antagonized by tetrodotoxin and markedly attenuated when extracellular calcium is removed. There is a significant correlation between the intracellular ATP concentration of the atrium and the ability to accumulate cyclic AMP in response to isoproterenol which suggests a causal relationship. Other possible mechanisms for batrachotoxin and veratridine inhibition of the cyclic AMP response are considered, and the possibility that calcium affects ATP pools critical for adenylate cyclase activity is discussed.

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ACKNOWLEDGMENTS I would like to acknowledge the excellent technical assistance of Martha Rietow and the skilled preparation of the manuscript by Sandra Dutky. Thanks to Dr. John Daly for his generous gift of batrachotoxin.