Molecular Pharmacology, Vol 17, 180-186, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Decreased Responsiveness of the Adenylate Cyclase System on Left Atria from Hypothyroid Rats

¹ Institute of Pharmacology, University of Essen, Hufelandstrasse 55, D-4300 Essen, Federal Republic of Germany

On isolated electrically driven left atria (37°, 1 Hz) of rats made hypothyroid by feeding 6-propyl-2-thiouracil the -sympathomimetic effects of isoprenaline and of phenylephrine—in the presence of 10⁵ M yohimbine—on force of contraction and on the cyclic AMP level were compared with those obtained on atria from euthyroid rats. In hypothyroid rats the dose-response curves for the positive inotropic effects of isoprenaline and of phenylephrine were shifted to the right by about 0.4-0.5 log unit. The positive inotropic effect evoked by Ca²⁺, however, was not affected by the hypothyroid state. On atria from euthyroid rats a submaximal effective concentration (EC₈₀ for the positive inotropic effect) of isoprenaline (30 nM) increased the cyclic AMP level by about 60% after 60 sec; in hypothyroid rats, on the other hand, the same concentration of isoprenaline produced only about a 25% increase in cyclic AMP. Phenylephrine (10^-5 M, the EC₈₀ for its positive inotropic effect) in the presence of 10^-5 M yohimbine increased in euthyroid rats the cyclic AMP level by about 25%, but failed to do so in hypothyroid rats. When used in three times higher concentrations, however, both agonists were capable of inducing increases in cyclic AMP that were comparable with the effects obtained in euthyroid rats. On atria from hypothyroid rats the basal as well as the isoprenaline- and NaF-stimulated activity of the adenylate cyclase was significantly lower than on atria from euthyroid rats. From these results it is concluded that the decreased sensitivity of cardiac -adrenoceptors in the hypothyroid state is due to the decreased responsiveness—at least in part—of the adenylate cyclase system linked to the -adrenoceptors. The results confirm the close correlation of the -sympathomimetic positive inotropic effect to the cyclic AMP generating system.

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ACKNOWLEDGMENTS The authors wish to thank Mrs. Gabriele Graf, Miss Mechtild Gröning, Miss Ulrike Jansen, Mrs. Doris Petermeyer and Mr. Erwin Hagelskamp for skillful technical assistance.