Thyroxine-induced changes in characteristics and activities of beta-adrenergic receptors and adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate systems in the heart may be related to reputed catecholamine supersensitivity in hyperthyroidism

Abstract

Modifications in characteristics and activities of beta-adrenergic receptors and certain parameters of the cyclic nucleotide systems were observed in the hypertrophied heart of the rat chronically treated with T4. These include: 1) an increased number of beta-adrenergic receptors without a change in their affinity, as determined by binding of (-)-[3H]dihydroalprenolol to the membrane; 2) increased sensitivity and magnitude of stimulation of adenylate cyclase in homogenates by isoproterenol, without a change in the basal or NaF-stimulated (total) enzyme activity; 3) decreased formation of cAMP and decreased activation of cAMP-dependent protein kinase in the minced heart stimulated by isoproterenol, probably due to decreased myocardial ATP concentration; 4) decreased activity of cAMP phosphodiesterase in the particulate fraction; 5) decreased activity of cGMP-dependent protein kinase in both the soluble and particulate fractions, accompanied by decreased activity of cAMP-dependent protein kinase in the particulate fraction; 6) decreased activity of the stimulatory modulator of cGMP-dependent protein kinase and, conversely, increased activity of the inhibitory modulator of cAMP-dependent protein kinase; and 7) increased sensitivity accompanied by decreased maximum tension development of the ventricular strip to contract in response to isoproterenol. These alterations largely disappeared upon regression of the hyperthyroid state. It is suggested that the above changes, many of which were the opposite of those reported earlier for the desensitized and hypertrophied rat heart caused by isoproterenol, may in part consitute the molecular basis for the reputed catecholamine supersensitivity of the heart in the hyperthyroid state.