Molecular Pharmacology, Vol 20, 190-194, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Xanthine Derivatives that Selectively Inhibit Cyclic GMP Hydrolysis Potentiate Cardiac Contractile Effects of Isoproterenol but Not Those of Bethanecol

¹ Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232

This study examines the abilities of xanthines to alter contractile and cyclic nucleotide responses to isoproterenol or bethanecol in left atria isolated from rabbits. Two of the xanthines studied (1-methyl-3-isobutyl-8-methoxymethylxanthine, and 1-methyl-3-isobutyl-8-t-butylxanthine) inhibited cyclic GMP hydrolysis more potently than cyclic AMP hydrolysis; another xanthine, theophylline, was equipotent at inhibiting the hydrolysis of the two cyclic nucleotides. All of the xanthines studied comparably potentiated contractile and cyclic AMP responses to isoproterenol (10^-8 M), regardless of their potencies to inhibit cyclic GMP hydrolysis. These data indicate that cyclic GMP is not antiadrenergic. The selective inhibitor, 1-methyl-3-isobutyl-8-methoxymethylxanthine, at a concentration that elevated cyclic GMP content to a level that was 3-fold above that observed with bethanecol alone, failed to depress contractile force, alter cardiodepressant effects of bethanecol, or alter atrial cyclic GMP content in the presence of this choline ester. These results demonstrate that the inhibition of cyclic GMP phosphodiesterase neither produces negative inotropic effects nor enhances the cardiodepressant effects of cholinergic agents.

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ACKNOWLEDGMENTS The authors wish to thank Drs. Joel G. Hardman and George L. Kramer for fruitful discussion and constructive criticism concerning this work.