Modulation by cortisol of adrenocorticotropin-induced activation of adrenal function in fetal sheep

We examined the hypothesis that cortisol (F) modulates the activation of adrenal function induced by treating fetal sheep in vivo with pulsatile ACTH (P-ACTH). Chronically catheterized sheep fetuses were infused in utero for 100 h between day 127 and day 131 of pregnancy with P-ACTH; P-ACTH plus metopirone; P-ACTH plus metopirone plus F; P-ACTH plus metopirone plus dexamethasone, or saline (controls). After 100 h, basal and ACTH-stimulated output of 11-desoxycortisol (S), F, and progesterone from collagenase-dispersed fetal adrenal cells was measured. Adrenal cells from fetuses treated with P-ACTH in vivo had significantly greater basal and stimulated (delta) outputs of F and S in vitro than controls. These effects were attenuated in fetuses pretreated with P-ACTH plus metopirone. Concurrent in vivo treatment with ACTH plus metopirone plus F restored basal and delta outputs of F and S to values that were not significantly different from those after P-ACTH alone. In vivo treatment with dexamethasone in addition to P-ACTH plus metopirone significantly raised basal outputs of F and S, but the cells were unresponsive to ACTH in vitro. Basal output of progesterone was significantly greater after in vivo P-ACTH plus metopirone plus dexamethasone, but no treatment raised delta progesterone output over controls. These results support a role for glucocorticoids in modulating ACTH-induced activation of adrenal function in late gestation fetal sheep.     

Adrenal dopamine-β-hydroxylase activity in the ground squirrel Citellus citellus—Effect of hibernation,arousal, and continuous light

In the hibernating ground squirrel activity of adrenal dopamine-β-hydroxylase was significantly lower as compared with the active animals (P < 0.01). The highest activity of this enzyme was found in animals tested immediately after arousal from hibernation (P < 0.01). The adrenal weight was higher in hibernating animals than in the active or aroused ones. The difference between the active and aroused animals was significant (P < 0.01). Extremely high enzyme activity was found in the adrenals of animals exposed to continuous light for 3 weeks as compared with active animals kept in continuous darkness or with controls subjected to a regime of 12 hr light-12 hr darkness (P < 0.01). The weight of the adrenals in the three groups was about the same level.     

Phenylethanolamine-N-methyl transferase activity in the avian adrenal following immobilization or adrenocorticotropin

The acute response of the avian adrenal to stress was evaluated by quantitatively measuring the adrenal and plasma levels of the major adrenal hormones (corticosterone (B), epinephrine (E), and norepinephrine (NE) along with assaying the adrenal activity of phenylethanolamine-N-methyltransferase (PNMT) in 8- to 9-week-old White Leghorn cockerels. The nonspecific stressor used in this study was a single 3-hour period of immobilization or a single dose of adrenocorticotropin (ACTH).It was found that the administration of ACTH or immobilization resulted in a significant increase in plasma E and NE concentrations with an accompanying decrease in their adrenal levels. ACTH-trcatment or immobilization was also effective in significantly increasing plasma B concentration and adrenal PNMT activity, but had no effect on the adrenal level of B.It is suggested that the rapid increase in PNMT activity, occurring with the acute application of stressors in chickens, may provide a means of sustaining an increased outflow of E in times of “stress.” The role that B may play in the elevation of PNMT, occurring in the avian stress response, is also discussed.     

The stimulatory effect of hypothalamic and mesencephalic tissue on the interrenal of tadpoles of Xenopus laevis Daudin.

Hypothalamic and mesencephalic tissues from juvenile toads of Xenopus, transplanted ventrally to the kidney of hypophysectomized tadpoles (Stage $\text{48}\text{49}$), increase the activity of Δ⁵-3β-hydroxysteroid dehydrogenase in the interrenals of the hosts as do pars distalis tissue or injection of mammalian ACTH. Enzyme activity was determined histochemically. Hypothalamic ACTH-like activity is not affected by hypophysectomy or by treating the donors with dexamethasone or metopirone. Therefore, the stimulatory effect seems to be due to a substance synthesized in the brain but different from CRH, octapeptides and presumably from serotonin and dopamine. In contrast, mesencephalic ACTH-like activity diminishes after hypophysectomy and dexamethasone treatment of the donors, so that hypophysial ACTH seems to be responsible for the ACTH-like effect of mesencephalic tissue on the larval interrenal.     

Phenylethanolamine N-methyltransferase in the brains of streptozotocin diabetic rats

Recent evidence suggests that adrenergic neurons in the brainstem and hypothalamus are important for regulation of endocrine and cardiovascular function and the response to stress. Since abnormalities in several of these functions are observed in diabetic subjects, we investigated the effects of streptozotocin-induced diabetes on the activity of the enzyme that converts norepinephrine to epinephrine [phenylethanolamine N-methyltransferase (PNMT)] in the brainstem and hypothalamus of the rat. Enzyme activity was measured in the supernatant of sonicated brain tissues of saline-treated control, diabetic, and insulin-treated diabetic rats. One month after streptozotocin treatment, increases in plasma glucose and food intake occurred; these were restored to control levels by insulin treatment. PNMT activity was approximately 2-fold higher in the brainstem of diabetic rats than in controls (P less than 0.0001), and administration of insulin partially prevented the effects of diabetes on PNMT activity (P less than 0.01 compared to diabetics and P less than 0.05 compared to controls). Brainstem enzyme activity measured in all animals (n = 53) exhibited a significant correlation with plasma glucose concentrations (r = 0.51; P less than 0.001). Diabetes had no apparent effect on PNMT activity in the hypothalamus. These findings are the first to suggest that experimental diabetes alters PNMT activity in the medulla/pons.     

The interrenal gland and ACTH and prolactin cells in the adenohypophysis of Monopterus and their roles in osmoregulations

The interrenal gland of the freshwater ricefield eel, Monopterus albus, consists of 3β-HSD-positive adrenocortical cell cords intermingled with groups of chromaffin cells; it lies in the haemopoietic tissues at the anterior tip of the head kidney and close to the posterior cardinal vein. Experimental studies using cortisol, metopirone, mammalian ACTH, and dexamethasone treatments show that ACTH and metopirone cause hypertrophy of the adrenocortical cells while cortisol and dexamethasone result in their atrophy; in the same experiments, the adenohypophyseal type-1 cells undergo hypertrophy in metopirone-treated animals but in the other three treatments there is cell regression and accumulation of cytoplasmic granules, showing that an endocrine feedback mechanism is in operation between the pituitary type-1 cells and the adrenocortical tissue. On the experimental evidence available, the adenohypophyseal type-1 cells in Monopterus are concerned mainly with adrenocorticotropic functions. Plasma electrolyte concentrations after the above treatments are also recorded, indicating an overall decrease in plasma sodium concentration after exogenous cortisol or ACTH administration. On the other hand, experiments involving administration of ovine-prolactin and reserpine, or alterations of the osmolarity and sodium concentration of the environment, show that prolactin is concerned with sodium and chloride conservation in this fish and that the pituitary type-2 cells in Monopterus are related to prolactin secretion. Thus the present report provides some experimental verification of the corticotropic and prolactin secreting roles, respectively, of the adenohypophyseal cell types-1 and -2 in Monopterus.     

High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas

Objectives Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA. Design Case control study. Patients We investigated 151 patients with SAA and 72 matched controls with normal adrenal computerized tomography. Measurements All participants had arterial blood pressure recorded, and serum cortisol and aldosterone measured before and after intravenous administration of 250 μg of ACTH, and following dexamethasone administration. Eighty‐three patients and all the controls had serum aldosterone and renin measured before and after saline infusion, and after a second saline infusion following dexamethasone administration. Results Using the mean + 2 SD values obtained from controls after dexamethasone administration and saline infusion following dexamethasone administration, normal cut‐off values for cortisol (30·11 nm ), aldosterone (67·59 pm ), and aldosterone/renin ratio (9·74 pm /mU/l) were developed. Using these cut‐off values, the estimated incidence of ACS and AAS in patients with SAA was 56·63% and 24·10%, respectively, whereas 12·05% had autonomous secretion of both cortisol and aldosterone. Systolic and diastolic arterial blood pressure correlated significantly with the aldosterone/renin ratio following ΑCTH stimulation (P < 0·0002 and P < 0·001, respectively), and after saline infusion following dexamethasone administration (P < 0·003 and P < 0·002, respectively). Conclusions By applying new cut‐offs, ACS and AAS in patients with a SAA is very common, and aldosterone secretion correlates with arterial blood pressure.     

Adrenocortical and Pituitary Glucocorticoid Feedback in Abstinent Alcohol‐Dependent Women

Background: The long‐term ingestion of alcohol diminishes hypothalamic–pituitary–adrenal (HPA) axis reactivity in alcohol‐dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol‐dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone. Methods: Seven women 4‐ to 8‐week abstinent alcohol‐only dependent subjects and 10 age‐matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 μg/kg), a synthetic ACTH (1–24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low‐dose cosyntropin was also administered following high‐dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes. Results: Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol‐dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone. Conclusion: Significant differences in pituitary–adrenal function were not apparent between alcohol‐dependent women and matched controls. Despite the small n, it appears that alcohol‐dependent women do not show the same disruptions in HPA activity as alcohol‐dependent men. These findings may have relevance for gender‐specific treatment effectiveness.     

Serum prolactin and luteinizing hormone levels and the activities of hypothalamic monoamine oxidase A and B and phenylethanolamine-N-methyl transferase are changed during sexual maturation in male rats treated neonatally with melatonin

Male rat pups were given a single dose of melatonin on day 5 of age. On days 30, 45, and 60, prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) were measured in serum and monoamine oxidase A (MAO A) activity, monoamine oxidase B (MAO B), and phenylethanolamine-N-methyl transferase (PNMT) activity were measured in the hypothalamus. Melatonin administration increased serum PRL levels at all ages studied. Serum LH levels were decreased in the melatonin treated group on day 30, but levels were elevated on days 45 and 60 of age as compared to controls. LH response to luteinizing hormone-releasing hormone (LHRH) only increased in melatonin treated animals at 30 days of age. Serum T levels decreased with melatonin treatment at 30 days of age, but increased on days 45 and 60 of age. T response to human chorionic gonadotropin (hCG) was blunted by melatonin treatment at 30 days of life. Hypothalamic MAO A activity increased, after neonatal melatonin administration, at 30 and 45 days of age and decreased at 60 days of life. Early neonatal melatonin administration increased MAO B and PNMT activities on day 45. These findings suggest that neonatal melatonin administration induces an earlier sexual maturation in male rats, possibly related to PRL, LH, MAO, and PNMT increases.     

Influence of corticosterone on the stress-induced elevation of phenylethanolamine-N-methyl transferase activity in the avian adrenal

The mechanism of adrenal phenylethanolamine-N-methyl transferase (PNMT) elevation occurring in the avian stress response was evaluated in 8- to 9-wk-old White Leghorn cockerels. The nonspecific stressor used in this study was a single 3-hr period of immobilization. The following physiological parameters were measured: (1) plasma and adrenal concentrations of epinephrine (E) and norepinephrine (NE); (2) plasma concentration of corticosterone (B); and (3) adrenal PNMT activity.It was found that if an inhibitor of B biosynthesis (Metopirone) was administered prior to the restraint period, the elevation in adrenal PNMT activity normally occurring with immobilization was prevented. The Metopirone-treated group also showed significantly smaller adrenal and plasma levels of E after restraint as compared to the non-drug-treated group. In contrast there was no significant difference between the restrained control group and the restrained group given Metopirone in their plasma and adrenal levels of NE.Puromycin given prior to immobilization was also effective in preventing the increased PNMT activity seen with immobilization. The administration of a large dose of B did not alter the blocking action of puromycin on PNMT elevation. The plasma concentrations of E and NE were also significantly smaller in the restrained group given puromycin as compared to the non-drug-treated restrained group.It is concluded that B does cause an increase in PNMT activity during the avian stress response and that this increase in activity provides a means for replenishing the adrenal with E under the condition of stress. The regulation of PNMT activity by B appears to be by enzyme induction.     

In vivo adrenocorticotropin (1-24)-induced accumulation of cyclic adenosine monophosphate by ovine fetal adrenal cells is inhibited by concomitant infusion of metopirone

Activation of the ovine fetal adrenal gland after pulse ACTH (P-ACTH) administration is associated with an increase in plasma cortisol levels. We have investigated whether cortisol may play a role in this adrenal activation process. The ability of fetal adrenal cells to accumulate cAMP in response to ACTH in vitro was compared in fetuses (day 132 of gestation) that had received infusions (100 h) in utero of 1) saline or saline + tartrate (0.5 ml for 15 min/2 h) (n = 4); 2) P-ACTH (66.6 ng/min for 15 min/2 h) (n = 4); 3) P-ACTH + metopirone (31.3 mg/h) (n = 4), to inhibit 11 beta-hydroxylase activity. Control fetuses showed no significant increase in plasma cortisol levels throughout the infusion and there was no significant accumulation of cAMP by fetal adrenal cells in vitro in response to ACTH. There was a significant (P less than 0.05) increase in plasma cortisol concentrations from 2.21 +/- 0.47 (mean +/- SEM) ng/ml at 0 h to 35.7 +/- 11.6 ng/ml at 96 h in fetuses receiving P-ACTH in vivo. In these fetuses there was a significant (P less than 0.05) accumulation of cAMP after addition of ACTH by fetal adrenal cells in vitro (mean increment delta = 48 pmol). This rise in plasma cortisol was prevented in fetuses receiving P-ACTH + metopirone. Further, metopirone treatment prevented the increase in fetal adrenal weight and accumulation of cAMP after in vitro ACTH that normally followed ACTH treatment in vivo. This effect was not overcome by further addition of guanylylimido-diphosphate. These experiments raise the possibility that cortisol might mediate the increase in cAMP accumulation resultant upon in vivo P-ACTH treatment.     

The fetal adrenals of the rat: correlations between growth, cytology, and hormonal activity, with and without ACTH deficiency.

Growth, ultrastructure, and corticosterone content were studied in the adrenals of rat fetuses in late pregnancy, between Days 19 and 21. In the fetuses of intact mothers, the hypophysial corticostimulating activity decreased between Days 19 and 21. Ablation of the fetal hypothalamus by total removal of the brain, leaving the hypophysis in situ (encephalectomy), induced atrophy of the adrenals, changes in adrenal ultrastructure, and decrease in the adrenal corticosterone content. Such modifications were also observed in response to the ablation of the pituitary gland by decapitation. The hypothalamus was involved in the control of ACTH release in late pregnancy. When mothers were adrenalectomized on Day 14, in the absence of hypothalamic tissue, the pituitary gland of the encephalectomized fetuses showed some corticostimulating activity; indeed, the adrenals of these fetuses were heavier on Day 21 than those of the decapitated fetuses but smaller than those of the littermate controls, and the adrenal corticosterone content was also greater than in the decapitated but less than in the controls. Encephalectomy induced modifications in adrenal cytology less marked than those induced by decapitation. These data suggest that the pituitary gland and the hypothalamo-hypophysial complex are the sites of the corticosteroid-induced inhibition of the corticostimulating activity of the fetal hypophysis.     

Opposite effects of ACTH and glucocorticoids on adrenal DNA synthesis in vivo.

Administration of ACTH to rapidly growing weanling rats results in an increase of DNA synthesis in adrenal and a decrease in liver. Dexamethasone administration decreases both adrenal and liver DNA synthesis. When both hormones were administered to the same animals, the liver DNA synthesis was similar to that observed with dexamethasone alone, but the DNA synthesis in adrenal was lower than that obtained with ACTH alone, yet higher than that observed with dexamethasone. The plasma levels of corticosterone were similar in animals treated with ACTH or with ACTH plus dexamethasone. Aminoglutethimide stimulated adrenal DNA synthesis, but less than ACTH. This substance overcame partially the inhibitory effects of dexamethasone on liver DNA synthesis but did not in adrenal. When both ACTH and aminoglutethimide were given simultaneously, adrenal DNA synthesis was higher than that observed with each substance alone. In all experiments in which adrenal cytosol DNA polymerase was studied, the activity varied in the same direction as DNA synthesis. These results indicate opposing effects of ACTH and glucocorticoids on adrenal DNA synthesis. The finding of a glucocorticoid effect on the adrenal is supported by the demonstration of a glucocorticoid specific binding protein in adrenal cytosol. Cycloheximide blocks the stimulatory action of ACTH on both steroidogenesis and DNA synthesis. Actinomycin D, as well as dexamethasone, blocks only the DNA synthesis-promoting action of ACTH. This latter result suggests some differences in the metabolic pathways by which ACTH controls steroidogenesis and growth in the adrenal cell.     

Reduced serum levels of dehydroepiandrosterone sulphate in adrenal incidentalomas: a marker of adrenocortical tumour

BACKGROUND AND OBJECTIVE Reduced serum levels of dehydroeplandrosterone sulphate (DHEAS) have been shown In patients with Cushing's syndrome resulting from adrenocortical adenoma, In contrast with normal DHEAS levels In patients with Cushing's disease. The elm of this study was to verify whether patients with incidentally discovered adrenocortical adenomas also have reduced levels of DHEAS. DESIGN Evaluation of serum DHEAS, serum and urinary cortisol, plasma ACTH and low dose dexamethasone suppression test In patients with adrenal Incidentaloma and Cushing's syndrome. PATIENTS Thirty-two patients with adrenal Incidentaloma and, as controls, 17 patients with overt Cushing's syndrome, were studied. RESULTS Serum DHEAS levels lower than normal were found In 21/24 (81.5 %) patients with adrenocortical Incidentaloma, but In only 1/8 patients with a mass of non-adrenocortical origin. This patient had massive bilateral metastatic infiltration of both adrenal glands and primary adrenal failure. The prevalence of low DHEAS levels in the two groups was significantly different (P= 00001). In patients with adrenocortical Incidentaloma, the prevalence of low DHEAS levels was significantly higher (P= 00001) than that found for some hormonal alterations Indicating pre-clinical hypercortlsoilsm (high urinary cortisol, unsuppressed serum cortisol after low dose dexamethasone administration and low plasma ACTH). Low DHEAS levels were found in all patients with Cushing's syndrome due to adrenocortical adenoma but in none of those with Cushing's disease. CONCLUSIONS Our results Indicate that the finding of low DHEAS levels can be considered a marker of the adrenocortical origin of an adrenal Incidentaloma, provided adrenal failure has been excluded.     

Hypertension induced by adrenocortical dysfunction--hypertension in 17 alpha-hydroxylase deficiency and metopirone-induced hypertension.

Hypertension in 17 alpha-hydroxylase deficiency was studied by comparing it with hypertension in Cushing syndrome or that in primary aldosteronism. Furthermore, the role of endogenous increases of ACTH, deoxycorticosterone, and 18 alpha-hydroxy-deoxycorticosterone upon blood pressure was studied in rats by administerating metopirone. Hypertension in 17 alpha-hydroxylase deficiency was considered to be more similar to that in primary aldosteronism from the studies on renin components, pressor responses to angiotensin II and norepinephrine, and renin responses to stimulations. Plasma catecholamines were slightly decreased in 17 alpha-hydroxylase deficiency. The hypertension was alleviated by the administeration of dexamethasone in 2 of 3 patients with 17 alpha-hydroxylase deficiency. However, in the remaining one who had an accelerated hypertension and normal renin, the hypertension was not alleviated by dexamethasone. In the animal studies, hypertension induced by metopirone was accelerated by salt loading of uni-lateral nephrectomy plus salt loading. In those rats, plasma ACTH, and deoxycorticosterone were markedly increased.     

Study of corticotropic function: respective values of short tests using metropirone and exogenous ACTH regardless of the hour administered

Basal plasma cortisol levels and adrenal responses to stimulation by endogenous and exogenous ACTH were compared between a group of controls and a group of patients with corticotrophic insufficiency. In addition, the adrenal response to the administration of exogenous ACTH was compared in each of these groups in relation to the timing of the test. There was a clear parallel between respective adrenal responses to exogenous ACTH and endogenous ACTH. Adrenal stimulation by exogenous ACTH may be used to investigate the residual secretion of endogenous ACTH and in the diagnosis or corticotrophic insufficiency, when a lesion interrupting functional hypothalamo-pituitary connections has been excluded. In the opposing case, use of a short test with metopirone is essential in order to confirm corticotrophic insufficiency. This test is better tolerated than the classical test and is not subject to sources of error due to urine collections.     

Cardiac epinephrine synthesis. Regulation by a glucocorticoid

BACKGROUND. The heart can synthesize epinephrine. Homogenates of rat heart, which contain the enzymes phenylethanolamine N-methyltransferase (PNMT) and nonspecific N-methyltransferase (NMT), methylate norepinephrine to form epinephrine. The cardiac atrium contains primarily PNMT and the cardiac ventricle contains both PNMT and NMT. METHODS AND RESULTS. Rats were given the glucocorticoid dexamethasone at doses ranging from 0.2 to 20 mg/kg. Twenty-four hours later, cardiac atria, ventricle, skeletal muscle, and adrenal had increases in PNMT activity to as much as 230% of baseline. NMT activity was unchanged. Longer-term treatment with 1 mg/kg dexamethasone daily for 12 days increased cardiac PNMT activity about fivefold and also increased atrial epinephrine levels. Dexamethasone did not alter ventricular epinephrine levels but increased levels of both PNMT and catechol-O-methyltransferase, the major catabolic enzyme for epinephrine. After dexamethasone treatment, greater volumes of anti-PNMT antiserum were needed to decrease PNMT enzymatic activity, indicating that dexamethasone treatment resulted in greater amounts of PNMT and did not just activate existing PNMT molecules. Denervation of the masseter muscle of rats by unilateral superior cervical ganglionectomy markedly diminished tissue norepinephrine and epinephrine levels but had no effect on masseter PNMT or NMT levels. We have previously shown that chemical sympathectomy with 6-hydroxydopamine increases cardiac PNMT levels. These findings suggest that PNMT is an extraneuronal enzyme in both cardiac and skeletal muscle. CONCLUSIONS. Glucocorticoids have several cardiovascular effects, including increased cardiac output and blood pressure. Enhanced cardiac epinephrine synthesis may mediate some of these glucocorticoid effects.     

Glucocorticoid regulation of growth hormone (GH) secretagogue-induced growth responses and GH secretagogue receptor expression in the rat.

Synthetic GH-releasing peptides such as GHRP-6 are potent GH secretagogues (GHSs) in several species, but attempts to stimulate growth by continuous GHS exposure have had limited success. GHSs also release ACTH and adrenal steroids. Since glucocorticoid excess is associated with poor linear growth, stimulation of the hypothalamo-pituitary-adrenal (HPA) axis by continuous GHS administration may compromise their growth-promoting effects. We have now examined the effects of continuous GHRP-6 infusion (100 mg/day, s.c. for 14 days) in normal 150-day-old female rats, and in adrenalectomized (Adx) rats with or without dexamethasone (Dex) replacement. Infusion of GHRP-6 did not significantly affect body weight gain compared with excipient-treated controls in either intact rats (controls, 9.0 +/- 1.6 vs GHRP-6, 11.8 +/- 0.9 g) or Adx rats (4.4 +/- 1.5 vs 7.9 +/- 2.7 g). However, GHRP-6 significantly increased weight gain in Adx rats treated with Dex (controls, 3.5 +/- 1.4 vs GHRP-6, 15.4 +/- 1.6 g;P<0.01). Adrenalectomy decreased plasma triglycerides (P<0.01), and Dex treatment increased plasma cholesterol (P<0.001), GHRP-6 treatment did not affect these plasma lipids. Dex treatment also reduced plasma GH-binding protein levels and hepatic GH binding (P<0.05). Pituitary GH content was decreased in Adx rats (P<0.05) but not in Dex-treated Adx rats. Adrenalectomy markedly decreased GHS-receptor mRNA expression in the arcuate (P<0. 001) and ventromedial nuclei (P<0.01), whilst Dex treatment normalized GHS-receptor expression. These results suggest that adrenal steroids are necessary for normal GHS-receptor expression and GHRP-6-induced weight gain, but long-term stimulation of the HPA axis by continuous GHS exposure may be detrimental to the growth response.     

HYPER-RESPONSIVENESS OF ALDOSTERONE TO METOCLOPRAMIDE IN ALDOSTERONISM

Metoclopramide, a dopamine antagonist, stimulates aldosterone secretion in normal man. We studied the response of plasma aldosterone, plasma renin activity, cortisol, sodium, potassium and serum prolactin to a 10-mg intravenous dose of metoclopramide in six dexamethasone suppressed patients with aldosteronism (four with adrenal adenoma, two with bilateral adrenal hyper-plasia) and in six dexamethasone suppressed normal male volunteers. All subjects were studied on an ad libitum sodium diet. Patients were supplemented with oral potassium prior to study. Sodium and potassium were not different between groups and did not change following metoclopramide. Cortisol was suppressed to less than 3 μg/dl throughout the study in all subjects. Basal plasma renin activity was significantly lower in the patients as compared with controls (P < 0·05), and did not change in either group following metoclopramide. Basal aldosterone levels were not significantly different in patients as compared with controls, although patients did tend to have higher levels. The incremental and integrated response of aldosterone to metoclopramide in patients was significantly greater than controls (P < 0·01). The percentage increase in aldosterone was greater than controls in five of the six patients. Basal prolactin was higher in the patients than in the controls. All subjects had a significant rise in prolactin to metoclopramide (P < 0·05). Five of six patients had an increased response of prolactin when compared to the controls and the four female patients had a significantly greater rise in prolactin as compared to the normals (P < 0·01). These data suggest that increased dopaminergic activity plays a compensatory role in inhibiting aldosterone secretion in patients with aldosteronism. It appears unlikely that a decrease of dopaminergic inhibition is involved in the pathogenesis of aldosteronism due to either adenoma or bilateral hyperplasia.