Control Of Corticosteroid Secretion Research Articles

Endothelins as local activators of adrenocortical cells.

Besides the classical corticotropic hormones, ACTH and angiotensin II, various regulatory peptides produced by the adrenal gland are thought to participate in the control of corticosteroid secretion. Here, we review the evidence that endothelins (ETs) synthesized within the adrenal cortex may act as autocrine and/or paracrine factors to regulate adrenocortical cell activity. The expression of ETs has been detected in normal, hyperplastic and neoplastic adrenocortical cells. The occurrence of ET receptors has been described in the different zones of the cortex. ETs stimulate the secretion of both glucocorticoids and mineralocorticoids, and modulate the proliferation of adrenocortical cells. The effects of ETs on steroidogenic cells are mediated through the activation of various signaling mechanisms including stimulation of phospholipase C, phospholipase A2 and adenylyl cyclase activity, as well as calcium influx through plasma channels. These observations suggest that locally produced ETs may play an important role in the regulation of corticosteroid secretion and in the control of mitogenesis in normal and tumoral adrenocortical cells.

Evidence for the involvement of nitric oxide in the control of steroid secretion by the frog adrenal gland

Nitric oxide (NO) has been found to modulate the response of rat, bovine and human adrenocortical cells to corticotropic factors. The aim of the present study was to investigate the possible involvement of NO in the control of corticosteroid secretion in the frog Rana ridibunda. Histochemical studies using the NADPH-diaphorase reaction and immunohistochemical labeling with antibodies against NO synthase (NOS) revealed that NOS is exclusively expressed in chromaffin cells. The NO donor sodium nitroprusside (SNP) and the NO synthase inhibitor Nw-nitro- l-arginine ( l-NO 2Arg) did not modify the spontaneous production of corticosterone and aldosterone by perifused adrenal slices. Similarly, l-NO 2Arg had no effect on the secretory responses induced by ACTH, angiotensin II (AII) and endothelin-1 (ET-1). In contrast, SNP significantly inhibited the stimulatory effects of ACTH, AII and ET-1 on corticosterone and aldosterone secretion. These data provide the first evidence for a modulatory role of NO on adrenocortical cell activity in amphibians.

The role of dopamine in the control of corticosteroid secretion and metabolism

The relation between aldosterone and its trophins is altered by electrolyte status and in some hypertensive conditions in man by a mechanism or mechanisms not understood. Dopamine has been suggested as the agent for the altered sensitivity of plasma aldosterone to angiotensin II based on the results of studies with dopamine itself, both in vivo and in vitro, and with pharmacological agonists and antagonists. The evidence derived from these studies is presented and discussed. Questionable specificity of the agents used makes interpretation difficult. Similarly, dopamine infusion rates used in man and animals have resulted in plasma concentrations far in excess of those found normally and these pharmacological concentrations have been shown to alter both the clearance rate of exogenous angiotensin II, and the pattern of steroid response to ACTH. Direct study of adrenal tissue has provided more promising results. The adrenal cortex possesses specific dopamine receptors and dopamine has been shown to modify aldosterone biosynthesis in vitro. Moreover, dopamine is present in adrenocortical tissue in concentrations in the range calculated to operate the receptors. However, there is, as yet, no evidence that dopamine concentrations change in a physiological meaningful way, for example, during changes in sodium status.

Role of dopamine in the regulation of aldosterone and 18-hydroxycorticosterone secretion in man.

This study was designed to investigate dopaminergic mechanisms involved in the control of corticosteroid secretion. Administration of the dopamine agonist bromocriptine (2.5 mg three times a day for 4 days) to 10 normal males suppressed (p less than 0.01) plasma 18-hydroxycorticosterone (18-OHB) responses to upright posture, isometric handgrip exercise, furosemide administration and angiotensin II infusion without altering supine blood pressure, electrolytes or plasma cortisol. Plasma 18-OHB responses to adrenocorticotropic hormone infusion were not altered by bromocriptine treatment. These observations suggest that angiotensin-mediated 18-OHB and aldosterone secretion is selectively inhibited by dopaminergic mechanisms. Thus, dopamine and angiotensin II may operate as opposing factors in the control of aldosterone biosynthesis.

Dopaminergic regulation of 18-hydroxycorticosterone and aldosterone secretion in man.

This study was designed to investigate dopaminergic mechanisms involved in the control of corticosteroid secretion. Plasma renin activity (PRA), prolactin, cortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycorticosterone (18-OHB) and aldosterone responses to metoclopramide 10 mg iv in the presence of a vehicle or dopamine (3 microgram/kg/min) infusions, or domperidone 10 mg iv were evaluated in 10 normal males. Metoclopramide, and the peripheral dopamine antagonist, domperidone both resulted in rises in serum prolactin levels. Metoclopramide, but not domperidone, resulted in parallel rises in plasma 18-OHB and aldosterone levels. Dopamine infusion markedly inhibited prolactin, 18-OHB and aldosterone responses to the central and peripheral dopamine antagonist metoclopramide. Administration of the dopamine agonist, bromocriptine, 2.5 mg three times a day for 4 days suppressed (P less than 0.01) mean 24 h plasma 18-OHB levels from 22.1 +/- 2.1 to 15.8 +/- 1.5 ng/dl. These results suggest that dopaminergic mechanisms modulate the secretion of 18-OHB and aldosterone. The circadian rhythm of 18-OHB secretion is not dependent on dopaminergic mechanisms.

Effect of metoclopramide and domperidone on aldosterone, 18-hydroxycorticosterone and prolactin secretion in the rhesus monkey

This study was designed to investigate dopaminergic mechanisms in the control of corticosteroid secretion. Eight rhesus monkeys received metoclopramide (200 μg/kg) or domperidone (200 and 400 μg/kg) with 5% dextrose (vehicle), or with dopamine (4 μg/kg/min) infusions begun 60 min before administration of the dopamine antagonist. Metoclopramide, in the presence of vehicle, increased plasma aldosterone concentrations from 4.8 ± 0.6 ng/dl to a maximum of 36 ± 4.7 ng/dl and PRL concentrations from 7.6 ± 1.1 ng/ml to a maximum of 120.5 ± 8.0 ng/ml. Administration of metoclopramide resulted in a rise in plasma 18-hydroxycorticosterone from 10.2 ± 1.3 ng/dl to a maximum concentration of 49.6 ± 4.5 ng/dl. Plasma concentrations of electrolytes, PRA, plasma cortisol, 11-deoxycorticosterone, corticosterone, 18-hydroxy-11-deoxycorticosterone, were not altered by metoclopramide. Domperidone, in both doses, markedly increased plasma PRL concentrations but had no effect on plasma 18-OHB or aldosterone concentrations. Dopamine infusion inhibited the aldosterone response to metoclopramide and the prolactin response to metoclopramide and domperidone. The results of this investigation demonstrate that aldosterone responses to metoclopramide and prolactin responses to metoclopramide and domperidone, are mediated by their antagonist activity at dopamine receptors.

Modulation of corticosteroid secretion by dopaminergic mechanisms in rhesus monkeys.

This study was designed to investigate dopaminergic mechanisms in the control of corticosteroid secretion. Ten rhesus monkeys received metoclopramide (1.25 mg iv) or domperidone (1.25 mg iv) with 5% dextrose (vehicle) or with dopamine (4 micrograms.kg-1.min-1) infusions begun 60 min before administration of the dopamine antagonist. Metoclopramide, in the presence of vehicle, increased plasma 18-hydroxycorticosterone from 11.2 +/- 1.0 ng/dl to a maximum concentration of 50 +/- 5.1, plasma aldosterone from 5.4 +/- 0.7 ng/dl to a maximum of 38.2 +/- 4.9, and prolactin (PRL) concentrations from 8.5 +/- 1.2 ng/ml to a maximum of 114.6 +/- 7.2. Domperidone, in the presence of vehicle, increased plasma PRL concentrations from 8.6 +/- 1.2 ng/ml to a maximum of 148.7 +/- 7.8 but had no effect on plasma corticosteroids. Dopamine infusion inhibited the 18-hydroxycorticosterone, aldosterone, and PRL response to metoclopramide and the PRL response to domperidone. These results demonstrate that 18-hydroxycorticosterone and aldosterone responses to metoclopramide and PRL responses to metoclopramide and domperidone are mediated by their antagonist activity at dopamine receptors. Domperidone may fail to stimulate aldosterone secretion because it does not cross the blood-brain barrier or fails to act as an antagonist at the glomerulosa dopamine receptor through which dopaminergic modulation of corticosteroid secretion is mediated. A parallel time course of stimulation of 18-hydroxycorticosterone and aldosterone secretion without changes in other aldosterone precursors suggests that dopamine modulates the activity of the glomerulosa 18-hydroxylase enzyme.

Altered dopaminergic modulation of 18-hydroxycorticosterone secretion in idiopathic edema: therapeutic effects of bromocriptine.

We have investigated dopaminergic mechanisms involved in the control of corticosteroid secretion in patients with idiopathic edema. The effects of treatment with the dopamine agonist bromocriptine (2.5 mg, three times a day for 5 days) on PRA, plasma cortisol, corticosterone, 18-hydroxycorticosterone (18-OHB), aldosterone, and PRL levels, and blood pressure responses to upright posture and isometric exercise were evaluated in nine patients with idiopathic edema and nine normal controls. Additionally, PRA and plasma cortisol, corticosterone, 18-OHB, aldosterone, and PRL responses to the dopamine antagonist metoclopramide were evaluated in both groups. Basal supine levels of PRA, cortisol, corticosterone, aldosterone, and PRL were similar in the two groups. However, plasma 18-OHB was considerably greater in the edema patients. Edema patients displayed greater orthostatic weight gain and greater 18-OHB and aldosterone responses to upright posture and isometric handgrip exercise. Bromocriptine treatment marke...

Dopaminergic Control of 18-Hydroxycorticosterone Responses to Posture, Isometric Exercise, and Diuretic Administration in Normal Man

This study investigates dopaminergic mechanisms involved in the control of corticosteroid secretion in man. The responses of plasma 18-hydroxycorticosterone (18-OHB) and aldosterone levels to upright posture and isometric handgrip exercise and furosemide administration as well as PRA and catecholamine responses to posture and exercise were evaluated in six normal subjects with and without bromocriptine (BEC) treatment. To evaluate the role of PRL suppression by BEC in affecting corticosteroid responses, we evaluated the effect of BEC on plasma 18-OHB and aldosterone responses to 20 mg furosemide in two subjects with autoimmune hypoprolactinemia. BEC (2.5 mg, three times a day for 4 days) markedly suppressed basal levels of 18-OHB, but not aldosterone, in the six normal subjects as well as the two subjects with autoimmune hypoprolactinemia. BEC also suppressed the 18-OHB and aldosterone responses to upright posture, isometric exercise, and furosemide administration without altering electrolytes, PRA, or plasma cortisol levels. Additionally, BEC suppressed basal levels of PRL, norepinephrine, and epinephrine as well as norepinephrine and blood pressure responses to upright posture and isometric exercise in the normal subjects. These results offer additional evidence that dopaminergic mechanisms modulate the secretion of 18-OHB and aldosterone, perhaps indirectly via inhibitory effects of dopaminergic pathways on catecholamine secretion.

Effect of domperidone, an extracerebral inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone, and 18-hydroxycorticosterone secretion in man.

This study investigates the dopaminergic mechanisms involved in the control of corticosteroid secretion in normal subjects. TSH, PRL, PRA, aldosterone, and 18-hydroxycorticosterone (18-OHB) were measured before and after the administration of domperidone (10 mg, iv) to eight healthy males. Domperidone, a selective peripheral dopamine antagonist, stimulated TSH and PRL secretion. Plasma concentrations of aldosterone, 18-OHB, cortisol, and PRA were not altered by domperidone. This is in contrast to previous observations of aldosterone, 18-OHB, and PRA responses to metoclopramide, a dopamine antagonist which readily crosses the blood-brain barrier. Domperidone may fail to stimulate aldosterone, 18-OHB, and renin secretion because it does not cross the blood-brain barrier or does not function as an antagonist for adrenal dopamine receptors modulating 18-OHB and aldosterone secretion.

The interaction of sodium and potassium status, of acth and of angiotensin II in the control of corticosteroid secretion

Publisher Summary This chapter describes interaction of sodium and potassium status of ACTH and of angiotensin II in the control of corticosteroid secretion. Angiotensin infusion at rates within the physiological range into normal human subjects increases the plasma concentration of aldosterone and its possible immediate precursor, 18-hydroxycorticosterone, but leaves the levels of other corticosteroids unchanged. In dose-response studies described in the chapter, individual angiotensin II-corticosteroid dose-response curves were constructed for 11-deoxycorticosterone (DOC), corticosterone, 18-hydroxy DOC, 18-hydroxycorticosterone, aldosterone, 11-deoxycortisol, and cortisol in sodium replete subjects, and again in the same subjects pretreated with dexamethasone to suppress endogenous ACTH. It was found that only 18-hydroxycorticosterone and aldosterone were affected in the first experiment, and this situation was unchanged in the dexamethasone-treated subjects. From the study, it was inferred that angiotensin II was capable of a much more general effect on corticosteroid secretion including stimulation of the zona fasciculata; that it must have at least one locus of action early in the biosynthetic pathway; and that the presence of ACTH is required for more catholic influence.

Circadian rhythm of plasma corticosteroids in heroin dependent subjects.

The circadian rhythm of corticosteroid secretion was investigated in six heroin dependent subjects by measuring plasma corticosteroids at 09.00 hours and 24.00 hours. All results were within the normal range and it seems unlikely that chronic heroin dependence affects the hypothalamic control of corticosteroid secretion.

Recent Advances in Endocrinology,

This is a well-edited collection of informed progress reports in endocrinology. The section on the central nervous system and the secretion of anterior pituitary trophic hormones is written by Mess and Martini. Their report includes an analysis of the evidence for short feedback control of certain pituitary trophic hormones (direct effect of trophic hormones on their own secretion) and the effects of hormones from certain target organs in causing release of pituitary trophic hormones. In the section on control of corticosteroid secretion, James and Landon suggest that there would be increased use of indwelling needles for studies requiring multiple blood samples if investigators served more frequently as experimental subjects. The sections on calcium (Foster and MacIntyre), glucose (Marks and Samols), thyroid (Galton), labor (Csapo and Wood), radio-immunoassay (Landon), renin (Brown, Fraser, Lever, and Robertson), and the cancer cell as an endocrine organ (Ross) are all well done. The section on