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Molecular Pharmacology, Vol 17, 73-78, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Xanthines and Skeletal Muscle: Lack of Relationship between Phosphodiesterase Inhibition and Increased Twitch Tension in Rat Diaphragms

G. L. KRAMER 1 and J. N. WELLS 1

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

No relationship was found between the abilities of a series of xanthine derivatives to increase twitch tension of directly stimulated rat hemidiaphragms and their abilities to inhibit hydrolysis in vitro of cyclic AMP or cyclic GMP or to change tissue levels of these cyclic nucleotides. The order of potency of the agents to increase twitch tension by 20% did not resemble the order of potency to inhibit either cyclic AMP or cyclic GMP hydrolysis. Further, a wide range of twitch tension responses was observed when agents were applied at concentrations that were five times those required for 50% inhibition of cyclic AMP and cyclic GMP hydrolysis. At concentrations that caused 20% increases in twitch tension, two of the agents were found to cause no significant changes in the tissue levels of cyclic AMP or cyclic GMP while two other agents caused significant increases in levels of both cyclic nucleotides. On the other hand, two agents that caused similar increases in cyclic AMP levels and no significant changes in cyclic GMP levels caused very different tension responses. Thus, under the conditions of this study, cyclic nucleotide metabolism does not appear to be involved in the mechanism of action of xanthines to increase twitch tension of rat diaphragms.

Note:
ACKNOWLEDGMENTS The authors wish to thank David Barnett for his expert technical help and Dr. Wolf-D. Dettbarn for performing the denervation surgery. We also wish to thank Drs. Wolf-D. Dettbarn, Joel G. Hardman, and Lynn Wecker for valuable discussion and constructive criticism.

Submitted on June 27, 1979
Accepted on August 30, 1979




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