2.ACTHの作用機序-特にAdrenergic Agentsの意義
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概要
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Cyclic 3′, 5′-AMP has now been established as an intracellular second messenger mediating many of the actions of a variety of different hormones including ACTH. The level of this nucleotide depends upon the relative activities of at least two enzymes, viz., adenyl cyclase, which is at first activated by each hormone and catalyzes the conversion of ATP to cyclic AMP, and phosphodiesterase, which catalyzes the breakdown of cyclic AMP to 5′-AMP. It has been recently reported that the metabolic effects of catechol-amines are differentially affected by alpha and beta adrenergic agents. Stimulation of the alpha adrenergic receptor inhibits, and stimulation of the beta adrenergic receptor enhances the effects of catecholamines on cyclic AMP accumulation probably via their effects on adenyl cyclase. This is also the case with vasopressin and MSH. Few deta have been reported about the role of an adrenergic receptor mechanism in adrenal steroidogenic response to ACTH.<BR>In the present study both alpha adrenergic blocker,, thymoxamine (5 to 50 μg/ml). and beta adrenergic stimulator, isoproterenol (1 μg/ml), were found to potentiate the rat adrenal steroidogenic response to ACTH in vitro, while both alpha adrenergic stimulator, methoxamine (1 to 20 μg/ml), and beta adrenergic blocker, alprenolol (10 to 25 μg/ml), to inhibit the response to ACTH. These results indicate that the general hypothesis (increase of hormone response by stimulation of the beta adrenergic receptor and decrease by stimulation of the alpha adrenergic receptor) may be valid in adrenal steroidogenic response to ACTH in vitro. Alpha adrenergic stimulator, phenylephrine (1 to 20μg/ml), and alpha adrenergic blocker, phentolamine (5 μg/ml), had no effect on the steroidogenesis induced by ACTH at the amounts used. Beta adrenergic blocker, propranolol (5 μg/ml), was shown to interefere with fluorescence of corticosterone by sulfuric acid-ethanol, resulting in the apparent potentiation of adrenal steroidogenesisby ACTH in vitro. Adenyl cyclase in rat adrenal homogenate was activated in the presence of isoproterenol and thymoxamine, and inhibited in the presence of propranolol, lending further support to the involvement of an adrenergic receptor mechanism in the adrenal. These adrenergic agents had no effect on phosphodiesterase activity. Prosta-glandin Ei (0.5 to 20μg/ml) was without effect on the steroidogenic response to ACTH. Omitting calcium from the medium and adding EGTA (1 mM) completely abolished the effect of ACTH on steroidogenesis and partially inhibited the dibutyryl cyclic-AMP-induced, steroidogenic response. Theophylline (1 mM) decreased rather than increased the steroidogenic action of ACTH and was without effect on the response to submaximal dose of dibutyryl cyclic AMP. On the contrary, imidazole (1 mM) potentiated the action of ACTH on steroidogenesis. These contradictory effects on adrenal steroidogenesis by ACTH may be explained by the possible action of these two agents on protein sythesis in rat adrenal tissue, a process which is essential for the steroidogenesis by ACTH. The fact that addition of cycloheximide (0.4 mg/ml) to medium inhibited completely the ACTH-induced steroidogenesis in vitro, also confirms the importance of new protein synthesis.
- 日本内分泌学会の論文