Thyroxine-Induced Changes in Characteristics and Activities of β-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.

β-Adrenergic Receptors and Catecholamine Sensitive Adenylate Cyclase in Developing Rat Ventricular Myocardium: Effect of Thyroid Status

“…Short term hyperthyroidism in the weanliig rat resulted in marked myocardial hypertrophy, a small but significant increase in Padrenergic receptor specific activity, no significant change in catecholamine dependent adenylate cyclase activation and more than doubling of the total /3-receptor number (per heart). The significance and mechanism of the lack of a n effect of hyperthyroidism on catecholamine-sensitive adenylate cyclase is unclear at present; however, the present finding is in general agreement with that reported in myocardium from adult hyperthyroid rats (17).…”

“…Numerous studies have also supported the interrelationships among increased thyroid gland activity, increased P-adrenergic sensitivity and increased numbers of myocardial P-adrenergic receptors during hyperthyroidism (3,6,(16)(17)(18)21). Indeed, exposure of the myocardium to thyroid hormone in vitro and the administration of pharmacologic concentrations of thyroid hormones in vivo result in myocardial hypertrophy and increased number of P-adrenergic receptors in various myocardial preparations (3,6,(16)(17)(18)21). In addition, Tse et al (17) demonstrated increased catecholamine-sensitive adenylate cyclase activity, decreased cAMP phosphodiesterase and decreased c-GMP dependent protein kinase activity in ventricles from hyperthyroid rats (17).…”

“…Indeed, exposure of the myocardium to thyroid hormone in vitro and the administration of pharmacologic concentrations of thyroid hormones in vivo result in myocardial hypertrophy and increased number of P-adrenergic receptors in various myocardial preparations (3,6,(16)(17)(18)21). In addition, Tse et al (17) demonstrated increased catecholamine-sensitive adenylate cyclase activity, decreased cAMP phosphodiesterase and decreased c-GMP dependent protein kinase activity in ventricles from hyperthyroid rats (17). These authors have suggested that changes in these various biochemical parameters may account for the increased P-adrenergic sensitivity found in the myocardium from hyperthyroid animals (17).…”

“…In addition, Tse et al (17) demonstrated increased catecholamine-sensitive adenylate cyclase activity, decreased cAMP phosphodiesterase and decreased c-GMP dependent protein kinase activity in ventricles from hyperthyroid rats (17). These authors have suggested that changes in these various biochemical parameters may account for the increased P-adrenergic sensitivity found in the myocardium from hyperthyroid animals (17). The role of hypothyroidism in the regulation of Padrenergic receptors in the heart has not been as extensively studied.…”

Beta-adrenergic receptor and cyclic AMP alterations in the canine ventricular septum during long-term norepinephrine infusion: implications for hypertrophic cardiomyopathy.

“…Tse et al 19 also reported that the increase in adenyl cyclase activity in the hyperthyroid rat heart was not accompanied by a change in cyclic AMP content. The explanation offered for this phenomenon was that a lower intracellular concentration of ATP prevented a significant increase in cyclic AMP formation.…”