Molecular Pharmacology, Vol 20, 179-189, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Selective Phosphodiesterase Inhibition and Alterations of Cardiac Function by Alkylated Xanthines

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

This study identified a series of alkylated xanthines with a range of potencies and selectivities as inhibitors of cardiac cyclic AMP and cyclic GMP phosphodiesterase activities. The potencies of these xanthines to inhibit phosphodiesterase activities of the rabbit atrial supernatant fraction were compared with the potencies of these agents to alter (a) spontaneous right atrial rate, (b) duration of left atrial contraction, and (c) contractile force of electrically paced left atria. Although the abilities of xanthines to increase heart rate or to shorten the duration of contraction were predictable from cyclic AMP phosphodiesterase inhibition data, abilities of xanthines to alter contractile force were not. No simple correlations were observed between inhibition of cyclic GMP phosphodiesterase in tissue extracts and alterations of any of the atrial functions. Failure to observe correlations in the present study, however, did not stem from a failure of xanthines to inhibit phosphodiesterase of intact cell preparations. Xanthines altered cyclic nucleotide contents of intact, functioning atria as predicted from their abilities to inhibit phosphodiesterase activities of the supernatant fraction. In addition, all xanthines potentiated contractile responses to isoproterenol, suggesting that the xanthines were capable of inhibiting phosphodiesterase activities relevant to contractile function. Thus, the present results, whule pointing to phosphodiesterase inhibition as the mechanism by which xanthines increase heart rate and shorten the duration of contraction, raise questions concerning the importance of phosphodiesterase inhibition in the effects of the xanthines on the force of contraction.

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ACKNOWLEDGMENTS The authors wish to thank David Barnett and Rebecca Sanderson for their expert technical help. We also wish to thank Drs. Joel G. Hardman, George L. Kramer, and Richard D. Olson for valuable discussion and constructive criticism.