Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems

Abstract

ABS TR A CT The mechanism responsible for the hyperdynamic circulatory state in hyperthyroidism has not been defined. Although certain cardiac manifestations resemble those caused by excessive adrenergic stimulation, recent evidence suggests that thyroid hormone exerts an effect on the heart that is independent of the adrenergic system. Since the inotropic and chronotropic effects of norepinephrine appear to be mediated by activation of adenyl cyclase, the possibility that thyroxine and triiodothyronine are also capable of activating adenyl cyclase was examined in the particulate fraction of cat heart homogenates.L-thyroxine and L-triiodothyronine increased the conversion of adenosine triphosphate-'P (ATP-P)to cyclic 3',5'-adenosine monophosphate-P (3',5'-AMP-'P) by 60 and 45% respectively (P<0.01). A variety of compounds structurally related to the thyroid hormones, but devoid of thyromimetic activity did not activate adenyl cyclase: these included 3,5-diiodo-L-thyronine, L-thyronine, 3,5-diiodotyrosine, monoiodotyrosine, and tyrosine. D-thyroxine activated adenyl cyclase and half maximal activity was identical to that of the L-isomer. Although the beta adrenergic blocking agent propranolol abolished norepinephrine-induced activiation of adenyl cyclase, it failed to alter activation caused by thyroxine.When maximal concentrations of L-thyroxine (5 X 10O moles/liter) and norepinephrine (5 X 10' moles/liter) were incubated together, an additive effect on cyclic 3',5'-AMP production resulted. This investigation demonstrates: (a) thyroid hormone is capable of activating myocardial adenyl cyclase in vitro and (b) this effect is not mediated by the beta adrenergic receptor. Moreover, the additive effects of norepinephrine and thyroxine suggest that at least two separate adenyl cyclase systems are present in the heart, one responsive to norepinephrine, the other to thyroid hormone.

The Influence of Thyroid Hormones on In Vitro Erythropoiesis

“…Evidence for such a hypothesis is provided by several observations. First, it has been proposed that thyroid hormone is capable of activating adenyl cyclase in vitro (10), although the concentrations were pharmacologic. In addition, 38-adrenergic responsiveness in hypothyroid rats is reduced (11), and phosphodiesterase activity correlates inversely with thyroid hormonal status (12).…”

“…Several studies suggest that thyroid hormones may also affect cell functions by increasing the intracellular concentration of cAMP (10)(11)(12). The observation that certain clinical manifestations of hyperthy-roidism may result from enhanced ,3-adrenergic responsiveness (13) is consistent with the hypothesis that thyroid hormones interact with receptors having , 8-adrenergic properties. This study examines the influence of thyroid hormones on in vitro erythropoiesis as well as the interactions of these hormones with catecholamine receptors.…”

Role of Adenosine 3′,5′-Monophosphate in Maturation of Fetal Lungs

“…41, 43, 53). Thyroid hormones also enhance concentrations of cyclic A M P in target tissues through stimulation of adenylate cyclase (37). Lung tissue studies of cyclic A M P metabolism have to date focused on responses to catecholamines, histamine, prostaglandin E , , and aminophylline.…”

Appearance of Hormone-sensitive Adenylate Cyclase in the Developing Human Heart

“…This finding was not significant and clearly more studies with complete doseresponse relations are needed t o clarify these observations. These findings do, however, lend further support t o the hypothesis that perhaps these two classes of hormones activate adenylate cyclase via different receptors (12,14,15,20,21). In preliminary studies with human fetal cardiac tissues stimulation of adenylate cyclase by glucagon and catecholamines was demonstrated a t 12-13 weeks of gestation' (3,19).…”

“…Tissues were normally obtained within 10 Receptor activation of myocardial adenylate cyclase by min after disrupti~n of the fetoplacental circulation, placed in hormones (catecholamines, histamine, and glucagon) with cold glycylglycine buffer (2 mM + 1 mM MgS04 + 0.2 mM concomitant production of adenosine 3',5'-monophosphate EGTA, pH 7.4), and returned to the laboratory: Enzymatic (CAMP) has been linked directly to glycogenolysis and investigations were conducted within 1 hr after obtaining the indirectly to positive chronotropic and inotropic effects (1 2, tissue. Extraneous connective tissue was dissected free and the 14,15,20,21). Robison et al (23) postulated that the hearts were blotted and rapidly weighed.…”