The factors that control adrenal steroid secretion and metabolism were investigated in rats made diabetic with Streptozotocin (65 mg/kg) and used one month after treatment. Diabetic animals possessed high resting levels of plasma corticosterone accompanied by adrenal hypertrophy; the showed an increased response to the stress of i.p. cold water injection. Moreover, the pituitaries of diabetic rats seemed to be releasing ACTH continuously and not storing it. Upon adrenal inhibition with Aminoglutethimide the expected increase in adrenal cholesterol and weight was of a smaller magnitude than in controls. The activity of liver enzymes that reduce ring A of corticosterone showed decreased activity in diabetics, which suggests that more corticosterone rather than its inactive metabolites were available to--but not able to suppress--the steroid feedback sites. The half-life of corticosterone in blood was similar in diabetes and controls. These results suggest that (a) diabetic animals were in a chronic stress condition; (b) the threshold for steroid feedback was less sensitive to variations in plasma corticosterone; (c) there is an abnormal peripheral disposal of corticosterone, but that other factors, besides the liver, regulate the clearance of the hormone from the circulation in the diabetic animals.
Male Wistar rats were treated with an i.v. dose of 100 mg/kg of Streptozotocin (STZ). Either 5 days or 1, 2 or 3 months after induction of diabetes, the adrenal function of these animals was studied. Short course diabetes (5 days) was accompanied by adrenal hypertrophy and high plasma corticosterone levels; during later periods the diabetic rats consistenly showed signs of adrenal hyperactivity, yet both adrenal weight and plasma corticosterone tended to be lower than in the 5 day-treated animals. Adrenal incubations with 14C-progesterone showed that 5 days and one month diabetic animals synthesized more deoxycorticosterone than controls; production of corticosterone and 18-hydroxydeoxycorticosterone was normal at all time periods studied. Synthesis of 18-hydroxycorticosterone, a compound which affects sodium metabolism, was increased in 5 day-treated rats; thereafter, the function of the zona glomerulosa seemed to be impaired in diabetic rats. These results suggest that early after induction of diabetes there is adrenal hyperfunction of the mixed type (i.e. gluco and mineralcorticoid), and that in the later periods (2-3 months), the deranged metabolism of the diabetic rat acts as a chronic stress.
The uptake of [3H]-aldosterone by the brain and anterior pituitary (AP) was studied after i.v. injection of the isotope into adrenalectomized rats. The AP showed the higher uptake ratio (i.e., radioactivity in tissue/radioactivity in blood), while the brain regions examined (hippocampus, hypothalamus, amygdala, cerebellum and cortex) contained lower levels of radioactivity, although they concentrated the hormone from blood. Neither [3H]-corticosterone nor [3H]-18-hydroxydeoxycorticosterone accumulated in the AP as much as [3H]-aldosterone, while [3H]-corticosterone's uptake was greatest in the hippocampus. Competition experiments demonstrated that [3H]-aldosterone uptake in the AP was inhibited by pretreatment of animals with excess aldosterone, corticosterone and dexamethasone, whereas aldosterone and corticosterone but not dexamethasone competed in the brain regions. Binding sites were demonstrated in vitro in cytosol fractions from AP and several brain regions. Scatchard plot analysis demonstrated high affinity, low capacity binding sites in cytosol from AP and hippocampus. These results suggest the AP and brain areas may be considered as targets for aldosterone, although the functions of the mineralocorticoid in these tissues are a matter of speculation.
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