Decreased responsiveness of the adenylate cyclase system on left atria from hypothyroid rats
Brodde, O.E.; Schümann, H.J.; Wagner, J.
Molecular Pharmacology 17(2): 180-186
1980
ISSN/ISBN: 0026-895X PMID: 6248755 Document Number: 157151
On isolated electrically driven left atria (37.degree. C, 1 Hz) of rats made hypothyroid by feeding 6-propyl-2-thiouracil the .beta.-sympathomimetic effects of isoprenaline and of phenylephrine, in the presence of 10-5 M yohimbine, on force of contraction and on the cyclic(c)AMP levels 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 .apprx. 0.4-0.5 log unit. The positive inotropic effect evoked by Ca2+, but was not affected by the hypothyroid state. On atria from euthyroid rats a submaximal effective concentration (EC80 [dose which produces 80% effectiveness] for the positive inotropic effect) of isoprenaline (30 nM) increased the cAMP level by .apprx. 60% after 60 s; in hypothyroid rats. The same concentration of isoprenaline produced only .apprx. 25% increase in cAMP. Phenylephrine (10-5 M, the EC80 for its positive inotropic effect) in the presence of 10-5 M yohimbine increased in euthyroid rats the cAMP level by .apprx. 25%, but failed to do so in hypothyroid rats. When used in 3 times higher concentrations, both agonists were capable of inducing increases in cAMP that were comparable with the effects obtained in euthyroid rats. On atria from hypothyroid rats the basal and the isoprenaline- and NaF-stimulated activity of the adenylate cyclase was significantly lower than on atria from euthyroid rats. The decreased sensitivity of cardiac .beta.-adrenoceptors in the hypothyroid state is due to the decreased responsiveness, at least in part, of the adenylate cyclase system linked to the .beta.-adrenoceptors. The close correlation of the .beta.-sympathomimetic positive inotropic effect to the cAMP generating system is confirmed.