Pharmacokinetic interaction with digoxin and glucocorticoids in rats detected by radio-immunoassay using a novel specific antiserum
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Prednisolone
Dexamethasone administration to rats decreases T4-5′-deiodinase activity in liver homogenates and slices and in isolated rat renal tubules. To determine if this decreased T4-5′-deiodinase activity results in decreased T3 production, rat livers and kidneys of control and dexamethasone-treated rats were perfused with medium containing free T4 concentrations approximating euthyroid rat serum, and net T3 production was measured by RIA. Dexamethasone administration decreased body weight by 14% but did not affect liver weight, kidney weight, or serum concentrations of T4 or T3. When livers were perfused with T4 concentrations of 10 μg/dl (free T4 = 6.5 ng/ dl), hepatic T3 production, T4 uptake, and the conversion of T4 to T3 were similar in dexamethasone-treated rats and salinetreated controls. However, when livers were perfused at a T4 concentration of 125 μg/dl (free T4 = 81 ng/dl), dexamethasonetreated livers produced significantly less T3 than controls because of decreased conversion of T4 to T3. Hepatic deiodination of T3 and excretion of T3 into bile were not affected by dexamethasone. Renal T3 production, T4 uptake, and conversion of T4 to T3 was likewise unaffected by dexamethasone treatment when kidneys were perfused at near-normal free T4 concentrations. These studies indicate that dexamethasone treatment does not alter T3 production in the perfused liver and kidney and underscore the importance of using free T4 concentrations approximating physiologic levels when studying regulation of T3 production in individual organs. (Endocrinology114: 31, 1984)
Reverse triiodothyronine
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Effects of dexamethasone on the hypothalamic-pituitary-thyroid axis in rats were studied. Rats given saline (group A), 25 micrograms of dexamethasone/100 g body weight (group B) or 500 micrograms o dexamethasone/100 g body weight (group C) were serially decapitated and brain tissues and blood were obtained. TRH contents in the hypothalamus, plasma concentrations of TRH, TSH, T4, T3 and reverse T3 were measured by specific radioimmunoassay. TRH contents in the hypothalamus were significantly increased at 3 h in group B after dexamethasone treatment. In group C, however, they significantly increased for 1 to 3 h, but then decreased with the minimum at 20 h. TRH plasma levels significantly increased with the maximum at 4 h in group B and at 24 h in group C. TSH plasma levels were significantly decreased initially and then significantly increased with the maximum at 5 h in group B and at 24 h in group C. TSH responsiveness to TRH was significantly decreased at 1 to 3 h in group B, but in group C it was significantly decreased initially and the significantly increased. T3 plasma levels significantly decreased at 1 to 3 h in group B and at 1 to 18 h in group C. Reverse T3 plasma levels were significantly increased with the maximum at 3 h in group B and at 6 h in group C. The results demonstrate that dexamethasone may act on multiple sites of the hypothalamic-pituitary-thyroid axis in rats and that its effect depends on the dose used or the time interval after dexamethasone treatment.
Hypothalamic–pituitary–thyroid axis
Group B
Group A
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We studied the effects of administration of dexamethasone, 2 mg orally every 6 h, for 5 days on the thyrotropin-releasing hormone (TRH)-induced release of prolactin (PRL), thyrotropin (TSH), triiodothyronine (T3) and thyroxine (T4) in 9 normal men and on the metoclopramideinduced release of PRL in 7 normal men. Dexamethasone suppressed the baseline serum levels of PRL, TSH and T3. The administration of dexamethasone blunted the PRL and TSH response to TRH; the blunted TSH response resulted in a decreased T3 and T4 response to TRH after dexamethasone. Following dexamethasone administration, the PRL response to metoclopramide, a dopamine antagonist which acts at the hypothalamicpituitary level to stimulate PRL secretion, was blunted in 7 normal men. The data suggest that short-term administration of pharmacological doses of glucocorticoids suppress the secretion of PRL and TSH by a direct effect on the anterior pituitary gland.
Metoclopramide
TRH stimulation test
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SUMMARY In order to obtain more insight into the mechanisms regulating endogenous ACTH secretion in humans we studied the inhibitory effect of acute i.v. dexamethasone administration on ACTH release under various conditions. Six male volunteers were subjected to six different protocols. After combined i. v. injection of 100 μg corticotrophin releasing hormone (CRH) and 100 μg growth hormone releasing hormone (GRH) there was the expected rise in ACTH (area under the curve, 1053 ± 204 (SE) (pmol/l) min) and cortisol (59788 ± 10098 (nmol/l) min) rise which was suppressed by prior i. v. injection of 2 mg dexamethasone (ACTH: 444 ± 63 (pmol/l) min; cortisol: 28528 ± 2152 (nmol/l) min). Insulin hypoglycaemia (IH) led to a more pronounced ACTH and cortisol rise compared with CRH (6307 ± 817 (pmol/l) min and 82080 ± 21934 (nmol/l) min, respectively) which was not completely suppressed by prior pretreatment with dexamethasone (ACTH, 580 ± 103 (pmol/l) min; cortisol: 55649 ± 5821 (nmol/l) min). Combined AVP/CRH injection (10 IU/100 fig) after pretreatment with dexamethasone (344 ± 41 (pmol/l) min for ACTH; 32832 ± 3173 (nmol/l) min for cortisol) could not reproduce the ACTH secretion following IH after pretreatment with dexamethasone (579 ± 103 (pmol/l) min for ACTH and 55649 ± 5821 (nmol/l) min for cortisol). In all subjects a saline control with 2 mg dexamethasone was performed. These findings confirm the acute inhibitory effect of glucocorticoids on CRH‐stimulated ACTH secretion. Since CRH‐induced ACTH secretion is almost completely abolished by administration of dexamethasone the ACTH rise following IH after dexamethasone can not be mediated by endogenous CRH alone. Moreover, since the addition of AVP to CRH (after dexamethasone suppression) could not reproduce the ACTH rise during IH after dexamethasone pretreatment, an additional, yet unknown factor stimulating ACTH secretion may be involved. In the same protocols, no significant difference could be observed comparing IH and GRH induced GH secretion (4948 ± 1172 (mU/l) min vs 3596 ± 820 (mU/l) min, NS); furthermore, in contrast to results obtained by chronic steroid administration, acute i. v. dexamethasone pretreatment did not affect IH or GRH‐induced GH secretion (4110 ± 666 (mU/l) min vs 2916 ± 462 (mU/l) min, NS). The GRH‐stimulated GH secretion (3596 ± 820 (mU/l) min) was not suppressed by prior intravenous treatment with dexamethasone (2916 ± 504 (mU/l) min, NS).
Corticotropin-releasing hormone
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In the present study the influence of dexamethasone treatment of rats on the basal values of thyrotrophin (TSH) and prolactin (PRL) and the response of both hormones to thyrotrophin releasing hormone (TRH) has been investigated. Male rats were given 100 μg of dexamethasone/rat for 8 days at the same time of day. Four hours after the last administration of dexamethasone 200 ng or 100 μg of TRH/rat was injected ip. Blood was collected 10 min later by decapitation. TSH and PRL were estimated by radioimmunoassay (RIA) using the NIAMD kits. The basal and TRH stimulated values of PRL in plasma were significantly lower in dexamethasone treated rats than in controls (P < 0.01). The basal TSH levels in the treated animals were also lowered (P < 0.05). After 200 ng TRH/rat the increase in TSH was not as high in both groups than after the administration of 100 μg/rat. There was no significant difference between the response of TSH to TRH in the dexamethasone treated and the control rats. The different effects of dexamethasone on PRL and TSH release after TRH may give a further insight into the different regulating mechanisms of both hormones in rats.
Basal (medicine)
TRH stimulation test
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Serum TSH and corticosterone concentrations were measured in intact rats and in rats given TRH or exposed to short-term cold 3 h and 12 h after pretreatment with dexamethasone in various doses. Dexamethasone given 3 h before experiemtns significantly depressed both TRH- and cold-induced TSH responses at all dose levels. Dose of 25 pg/100 g body weight significantly depressed serum TSH concentration when given 3 h before the experiment. However, when given 12 h before the experiment the drug augmented TRH-induced TSH secretion, although the cold response was unaltered. In intact rats dexamethasone significantly depressed serum TSH concentration in doses of 250 and 500 mug/100 g body weight. In all experiments the steroid blocked ACTH secretion. These results support the view that the effect of dexamethasone on thyroid function is highly dependent on the time relations. A single large dose of dexamethasone has first an inhibitory effect at the pituitary level and then facilitates pituitary to TRH and at the same time inhibits secretion of TRH in response to cold.
TRH stimulation test
Corticosterone
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A fast and direct effect of dexamethasone on liver metabolism is reported. In the perfused rat liver, addition of dexamethasone directly to the perfusate is followed by an increase in the level of free fatty acids (FFA) and glycerol. These effects of dexamethasone are evident within 30 minutesof hormone administration. The response to dexamethasone in livers from normal and adrenalectomized rats is similar. While dexamethasone and glucagon both had a lipolytic effect, these effects are not additive.
Steroid hormone
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Serum TSH and corticosterone concentrations were measured in rats given TRH or exposed to short-term cold, as well as in intact rats, after pre-treatment with dexamethasone for six days at two different dose levels (25 and 250 mug/100 g body weight). Both doses increased the secretion of TSH in response to TRH whereas cold-induced TSH secretion was not modified by pre-treatment with dexamethasone. In intact rats serum TSH levels did not differ significantly from controls. In all experiments the steroid blocked ACTH secretion. It was also found that administration of TRH produced a rise in serum corticosterone concentrations. Our results support the view that dexamethasone given for six days facilitates TRH stimulation of the pituitary whilst simultaneously inhibiting the secretion of TRH in response to cold.
Corticosterone
TRH stimulation test
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