Functional tests of the adrenal cortex.
Komrad, Eugene Leslie
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Under conditions of general body stress, the adrenal medulla is called upon to secrete its hormone, epinephrine. As a result of the influences of this hormone , a variety of changes in the resting physiology of the organism are incurred, which usually aid the individual in meeting the stressful challenge. One of the first changes which is known to occur as a result of the action of endogenous or exogenous epinephrine is a generalized hyperglycemia. Although this fundamental observation has been known for half a century, a complete understanding of the mechanism of action is still lacking . In the fasting animal, it could logically result from an increased liver glycogenolysis and/or a decreased glucose uptake by the tissues. A review of the literature has shown that whereas all workers are agreed on an increased liver glycogenolysis as a result of epinephrine activity, they are far from agreement on the latter phase, the glucose uptake. The results of this study indicate that much of the confusion is due to a misuse of terms, for it has been demonstrated that, at least in vitro , the glucose uptake of muscle tissue increases, while the amount of glucose utilized decreases following epinephrine. The extra glucose is stored in the form of hexosemonophosphate. There have recently been made available a number of compounds belonging to the aryl-2-haloalkylamine series, of which Dibenamine is a type compound, which have the ability to inhibit many of the actions of exogenous or endogenous epinephrine. For this reason, they are known as adrenergic blocking drugs. It was of interest to study a number of these compounds to determine their ability to inhibit epinephrine-induced hyperglycemia . A standard intravenous dose of 4 gamlnu/ kg. was used as the challenging dose of epinephrine on the basis of a dose-response curve and the previous report that it was within physiologic range. The following compounds were tested. They are listed by the aryl portion of' the molecules: 2-orthobenzyl phenoxyethyl; l-phenyl-2-N-methylbenzyl; 9-fluorenyl; 1-naphthylmethyl; methylthionaphthalene; 2-biphenylyloxy; benzhydryl ; and one dihydrogenated derivative of ergot, dihydroergocornine . It is suggested that the effectiveness of 2-haloalkylamines in diminishing or blocking epinephrine-induced hyperglycemia in rabbits is roughly related to their potency as measured by antagonism of the other effects of epinephrine. The basis of this suggestion is that the most potent drugs block or diminish the blood sugar rise in a dose of 2 mg./kg., while the less potent homologues require a dose of 5 mg. /kg . t o obtain the same effect. The least potent of these agents did not reduce the hyperglycemia even in a dose of 10 ms ./kg. In addition , the methyl homololgue of one of the adrenergic blocking drugs is known to have a markedly reduced epinephrine antagonism, and did not have any effect on the hyperglycemia . Likewise, when the halogen is replaced by an hydroxyl radical, and the resulting agent loses its epinephrine reversal action, it also loses its ability to block epinephrine induced hyperglycemia. A reviewer of the literature, together with the data obtained, seems to indicate that it is a general property of the adrenergic blocking drugs to inhibit the hyperglycemic effect of epinephrine in the rabbit. Also, it is to be expected that larger doses of blocking drug are required to inhibit epinephrine-induced hyperglycemia than epinephrine-induced hypertension. The hypertensive action of epinephrine is due to an algebraic summation of a pressor and depressor phase . Hence, a slight inhibition of the pressor response becomes magnified by the depressor action. However, in the glycemic effect of epinephrine, only a hyperglycemic phase is present, and would require larger doses of blocking drug to induce an equivalent diminution to that found in the blood pressure response. [Truncated]
Thesis (M.A.)--Boston University