Abstract

Rats whose adrenergic nerve function has been blocked are similar to adrenalectomized rats in their responses to external stimuli that require an increased expenditure of energy. The basal metabolism is almost normal; but on exposure to cold or to muscular work, neither animal can elicit piloerection, vasoconstriction or shivering; nor do they show lipolytic or glycogenolytic responses to epinephrine. The finding that epinephrine fails to restore these responses in adrenalectomized animals indicates that the incapacity of these animals to withstand cold or strenuous work results from failure of sympathetic target organs to respond to transmitted messages. Communications are re-established by aldosterone as well as glucocorticoids, suggesting that the inexcitability of adrenergic receptors after adrenalectomy is related to changes in electrolytes.

An important contribution to biology has been the concept of Sutherland and co-workers that cyclic 3',5'-AMP is the chemical trigger mediating catecholamine action in sympathetic target organs. These authors have outlined the various steps in the activation of phosphorylase by catecholamines. Some of the steps in the activation of another sympathetic function, the breakdown of triglycerides to FFA, may be outlined as follows:

Catecholamines stimulate lipolysis by causing an instantaneous activation of adenyl cyclase, thereby increasing the steady-state level of cyclic 3',5'-AMP. This response, however, is limited by the destruction of cyclic 3',5'-AMP by phosphodiesterase. On the other hand, the steady-state level of cyclic 3',5'-AMP is increased still further by theophylline, which inhibits phosphodiesterase. As a result, lipase is activated to a much greater extent by theophylline than by the catecholamines.

The effect of catecholamines is inhibited by such diverse compounds as beta-adrenergic blocking agents and nicotinic acid. The beta blocking agents act by competitively blocking catecholamines at adenyl cyclase, whereas the inhibitory effects of nicotinic acid appear to be due, at least in part, to stimulation of phosphodiesterase. This action would explain why nicotinic acid has such a marked effect on the basal output of FFA. In addition, the effects of catecholamines are prevented by adrenalectomy, presumably through lack of proper ionic environment at the receptor site.

Finally, treatment with thyroid hormone induces the formation of additional adenyl cyclase; in contrast, thyroidectomy reduces the amount of enzyme. In neither case is the amount of lipase affected. Should these effects on the fat pad be typical of other thyroid functions, the interplay between these systems could be explained by a given amount of catecholamine activating a larger amount of adenyl cyclase. As a logical extension of this view, certain actions of thyroid hormones should be diminished after sympathectomy. This might explain why certain sympatholytic agents produce ameliorative effects in patients with hyperthyroidism.