Effects of corticotropin-releasing factor (CRF) on aldosterone and 18-hydroxycorticosterone in essential hypertension and primary aldosteronism

The effects of ovine corticotropin releasing factor (o-CRF) on plasma aldosterone, 18-OH-corticosterone (18-OHB), plasma adrenocorticotropin (ACTH) and cortisol were determined in eight patients with primary aldosteronism, six with aldosterone-producing adenoma (APA) and two with idiopathic hyperaldosteronism (IHA). The results were compared with those in six normal subjects and eleven patients with essential hypertension (EHT, 5 with low renin and 6 with normal renin). In patients with APA, the peak plasma aldosterone and 18-OHB responses to 100 micrograms iv of o-CRF (226% and 113% increase from baseline, respectively) were greater than those in EHT and normal subjects. The net integrated aldosterone and 18-OHB responses (840 +/- 156, and 419 +/- 121 ng/dl.hr, respectively) were also significantly greater (p less than 0.01) in APA than those in normals and EHT. In two patients with IHA, both the peak and net integrated aldosterone response were smaller than those in APA, in spite of nearly identical plasma ACTH and cortisol responses. These results suggest that augmented responses of mineralocorticoids to o-CRF may be characteristic of aldosteronism due to APA, mediated by CRF-induced ACTH, and possibly other proopiomelanocortin (POMC)-derived peptides.     

Age-related changes in the dog hypothalamic-pituitary-adrenocortical system: neuroendocrine activity and corticosteroid receptors.

Aging is associated with a progressive dysfunctioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We have studied the response of the HPA axis to stress and a hormonal (ovine corticotropin releasing factor (o-CRF) challenge in young (1.5-2 years) and aged (greater than 11 years) dogs. Compared to the young dogs, the aged animals displayed an increased basal concentration of both ACTH and cortisol. In addition, in response to an o-CRF challenge (1 microgram/kg i.v.) or an electric footshock (1 mA, alternatively on/off for 2 s) or immobilization (45 min) stress, the aged dogs showed significantly larger increments in ACTH and cortisol. Following the challenge test, the young and aged dogs reached their respective basal hormone levels at the same time, except for the o-CRF test. In the latter case, in contrast to the young controls, the aged dogs still showed an increased plasma cortisol level compared to the pre-challenge basal hormone concentration. Concerning the effect of aging on the brain and hypophyseal corticosteroid receptors, a selective decline (minus 50-75%) in mineralocorticoid receptor (MR) was observed in all measured brain regions (dorsal and ventral hippocampus, septum, hypothalamus) and anterior pituitary, whereas no change was found in brain glucocorticoid receptor (GR) number. The GR level in the anterior pituitary was even increased by 70%. In light of the role that MR and GR seem to play in the regulation of the HPA axis, it is concluded that the diminished MR number in the aged dog brain may underly the increased basal hormone levels and the elevated responsiveness of the HPA axis in these animals. The observation that the stress-induced elevations of cortisol and ACTH were not prolonged at senescence suggests that the GR-mediated negative feedback action of glucocorticoids is not altered, which is in line with the unchanged brain GR numbers in the aged dogs.     

Structure-activity relationships of monomeric and dimeric synthetic ACTH fragments in perifused frog adrenal slices

The effect of synthetic monomeric and dimeric ACTH fragments on spontaneous and ACTH(1-39)-evoked steroidogenesis in frog interrenal tissue was studied in vitro. Infusion of ACTH fragment 11-24 (10(-6) M) or its dimeric conjugates, attached either by their N-terminal, Glu(11-24)2, or their C-terminal amino acid, (11-24)2Lys, had no effect on the spontaneous release of corticosteroids. The monomer ACTH(11-24) and the dimer Glu(11-24)2 were also totally devoid of effect on the steroidogenic response to ACTH(1-39) (10(-9)M). In contrast, the (11-24)2Lys conjugate (10(-6)M) significantly decreased ACTH-induced stimulation of corticosterone and aldosterone (-63 and -62%, respectively). The dimeric conjugate of the fragment ACTH(7-24), linked through the C-terminal ends, (7-24)2Lys (10(-6)M), was also completely devoid of effect on basal steroidogenesis but caused a marked decrease of ACTH-evoked corticosterone and aldosterone release (-72 and -80%, respectively). Conversely, infusion of the dimer (1-24)2Lys gave rise to a dose-related stimulation of corticosterone and aldosterone release. The time-course of the steroidogenic response to the dimer was similar to that of ACTH(1-24). The 1-24 conjugate was 70 times less potent than the monomers ACTH(1-24) and ACTH(1-39). These results suggest that amphibian adrenocortical cells contain only one class of ACTH receptor which recognizes the 11-24 domain of ACTH with an affinity which depends on the presence of a strong potentiator segment, located at the N-terminus end of ACTH(1-39). Since the ACTH-dimers are thought to induce cross-linking of the receptors, our results suggest that aggregation of ACTH receptors causes a down-regulation of the receptors.     

Angiotensin II increases ACTH release in the absence of endogenous arginine-vasopressin

Recent studies from our laboratory indicate a primary central site of action of Angiotensin II (AII) to release ACTH. The present studies were designed to test whether AII is able to release ACTH in vivo in a similar fashion in intact, cannulated, freely moving Long-Evans (LE) or in vasopressin (AVP)-deficient, Brattleboro (DI) female rats. The in vivo response to AII was compared with that elicited by synthetic CRF. AII injected i.v. (0.4 or 2 micrograms/100 g BW) induced a significant, dose-related increase in plasma ACTH values 5 and 15 min after injection, in both LE and DI rats. CRF given to LE and DI rats at 0.4 micrograms/100 g BW elicited a larger increase in ACTH plasma values than a similar dose of AII, 5 or 15 min after the injection. Moreover, ACTH levels after CRF in DI rats were significantly greater than those obtained in LE controls. In vitro studies using dispersed anterior pituitary cells indicate that the response of cells from either LE or DI rats to AII or AVP (both at 10(-9) and 10(-8)M) was similar. Cells from DI donors were hyperresponsive to CRF (2 X 10(-11) and 10(-10)M) in terms of ACTH release when compared with the response of cells from LE rats. The present results suggest that the presence of AVP is not essential to mediate the central response to AII and that AII may act centrally to stimulate CRF release from the hypothalamus in vivo, which would then enhance ACTH output. The results in the DI rat indicate that the increased response to CRF may be an important compensatory mechanism involved in the regulation of adrenocortical function in the DI rat.     

The effect of MSH/ACTH 4-10 on delayed response performance and post-test locomotor activity in rats

Delayed response performance was measured in male, Long-Evans rats 1 hr after IP administration of various doses of MSH/ACTH 4-10 or control in a Hunter delayed reaction apparatus. Additional treatments consisting of naloxone 500 micrograms/kg (IP) and naloxone 500 micrograms/kg in conjunction with MSH/ACTH 4-10 95 micrograms/kg were also administered. Directly after delayed response performance was assessed, gross locomotor activity was determined. MSH/ACTH 4-10, at a dose of 95 micrograms/kg, significantly enhanced retention of a visual stimulus, while MSH/ACTH 4-10, at doses of 195 and 285 micrograms/kg, significantly impaired delayed response performance. Naloxone treatment resulted in significantly impaired delayed response performance when compared to control. However, naloxone plus MSH/ACTH 4-10 treatment failed to produce a significant difference from control in the delayed response performance paradigm. In post-test locomotor activity determination, an apparent dose-response existed for MSH/ACTH 4-10 with the two highest doses (190 and 285 micrograms/kg) resulting in significantly increased locomotor activity. The observed delayed response performance data support theories implicating MSH/ACTH peptides in attentional processes involving visual stimuli. The fact that large doses of MSH/ACTH 4-10 disrupt delayed response performance while increasing post-test activity suggest that an optimum level of effect caused by the MSH/ACTH peptide exists in this paradigm.     

The possible involvement of cytochrome P-450 monooxygenase in AVP-induced ACTH secretion

AVP (10(-7) M) induced ACTH as well as PGE2 release from rat anterior pituitary quarters. Inhibitors of P-450 monooxygenase, metyrapone (10 mM) and piperonyl butoxide (1 mM and 10 mM) attenuated the ACTH and PGE2 response to AVP. 7,8-benzoflavon (10 mM) which inhibits 3-methylchloranthrene inducible form of P-450 isoenzymes showed no inhibition of AVP-induced ACTH secretion. The decrease in ACTH response to AVP was still observed following the inhibition of prostaglandin synthesis by indomethacin. These results suggest that cytochrome P-450 monoocygenase systems are involved in the process of AVP-induced ACTH secretion, 3-methylchloranthrene inducible form of P-450 isoenzymes do not seem to be involved in this process.     

Running training attenuates the ACTH responses in rats to swimming and cage-switch stress.

The present study was carried out to investigate the effect of running training on adrenocorticotrophic hormone (ACTH) response in rats to swimming or cage-switch stress to determine whether, after physical training, a cross-adaptation develops in the ACTH responses induced by different types of stresses. Rats were trained by two different kinds of exercises and for two different periods of training: 1) swimming for 4 wk (4W-swimming), 2) running for 4 wk (4W-running), and 3) running for 10 wk (10W-running). Remaining rats were used for control for 4 wk (4W-control) and 10 wk (10W-control). The ACTH response induced by swimming stress was reduced after training by swimming (62.4%) or by running (13.8-16.4%). These training periods also attenuated the ACTH response induced by cage-switch stress (62.4% in the swimming group, 23.8-34.6% in the running groups). After swimming stress, the 4W-swimming and 10W-running groups showed smaller increases in blood glucose than the control groups. In addition, the increased levels of blood lactate in all the trained rats were significantly smaller than those in the control groups, suggesting that an adaptation was achieved after physical training. These results suggest that after running training, cross-adaptation is developed in the ACTH response induced by different types of physical (swimming) or psychological (cage-switch) stresses.     

Circadian variations and extraadrenal effect of ACTH on insulinemia in rabbit.

The present experiment was designed to study the action of ACTH1-24 on insulin secretion during the circadian cycle in normal rabbits and to provide evidence that ACTH1-24 has an extra-adrenal effect on this secretion. In normal rabbits intravenous administration of three doses of ACTH1-24 (1, 10, 100 micrograms/kg) at 10 a. m. increased plasma insulin levels. Hyperglycemia only occurred with doses of 10 and 100 micrograms/kg. A maximum insulin response was already obtained at 1 micrograms/kg. The same experiment performed at 12 p. m. also induced hyperinsulinemia which was only noted at 10 and 100 micrograms/kg; hyperglycemia was only observed after stimulation by the highest dose (100 micrograms/kg). ACTH was therefore more effective during the day; however, at 12 p. m. plasma insulin levels were the highest, but only with the maximum dose of ACTH (100 micrograms/kg). The effect of ACTH1-24 was evaluated throughout the day on normal and adrenalectomized rabbits. In normal animals injection of ACTH1-24 increased plasma glucose and insulin levels both together. In the contrary, in rabbits deprived of adrenal glands, ACTH1-24 induced high insulinemia along with hypoglycemia. We could, therefore, reasonably conclude that ACTH stimulates directly the pancreatic secretion of insulin.     

Presence of ACTH and its receptor on a B lymphocytic cell line: a possible autocrine function for a neuroendocrine hormone

A mouse B lymphocytic cell line, designated BCL1, was found to produce immunoreactive ACTH and to secrete this molecule into culture supernates. The BCL1-derived ACTH induced Y-1 adrenal cells to undergo a steroidogeneic response and was eluted from gel filtration columns at a molecular weight similar to that expected for pituitary-derived ACTH. Furthermore, ACTH receptors were detected on the surface of BCL1 cells using indirect immunofluorescence and 125I-ACTH binding studies. Scatchard analysis demonstrated the presence of high and low affinity binding sites with dissociation constants of 4.5 x 10(-12) M and 2.8 x 10(-9) M, respectively. The production of both ACTH and its receptor by this B lymphocyte cell line suggests that an autocrine mechanism might be important for the maintenance of the transformed phenotype.     

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Objective: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients.Methods: Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed.Results: EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN.Conclusion:The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas.Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol     

Compared effects of ACTH, angiotensin II and POMC peptides on isolated human adrenal cells

Human adrenocortical tissue obtained, on eight occasions, at the time of nephrectomy for renal carcinoma (outside the adrenal pole) was treated by collagenase to dissociate the cells. These were hen submitted to a short, 2-h, incubation with the N-terminal fragment (16 K) of POMC, its derivative, gamma 3-MSH, beta-lipotropin and beta-endorphin, in parallel with ACTH 1-24 (Synacthen Ciba) and angiotensin II (AII, Hypertensin Ciba). Under the influence of ACTH (10(-10) M), and AII (10(-10) M), basal glucocorticoid output, including more than 80% cortisol, was increased by factors of 3 +/- 0.51 (SEM) and 1.35 +/- 0.12 (SEM), respectively. The corresponding aldosterone responses were 1.60 +/- 0.13 for ACTH and 1.38 +/- 0.09 for AII. With the exception of gamma 3-MSH, the POMC peptides under study had no steroidogenic effect. gamma 3-MSH (10(-9) M) and AII (10(-10) M) stimulated aldosterone production to approximately similar levels of, respectively, 1.23 +/- 0.05 and 1.38 +/- 0.09 times the basal production. In contrast to AII however, gamma 3-MSH showed no apparent effect on glucocorticoid output. Steroidogenic response to ACTH was potentiated by gamma 3-MSH at a concentration of 10(-10) M which, when used alone, proved ineffective. This potentiating effect was pronounced for the aldosterone response, whereas the glucocorticoid production was hardly affected. This action ceased to be visible when the cells reached maximal stimulation by ACTH. These findings suggest that gamma 3-MSH--a portion of the 16 K fragment--may have a possible role in aldosterone secretion.     

Interleukin-1 potentiates basal and AVP-stimulated ACTH secretion in vitro--the role of CRH pre-incubation.

The acute-phase cytokine interleukin-1 (IL-1) is known to activate the hypothalamic pituitary adrenal axis, primarily via corticotropin releasing hormone (CRH). The aim of this study was to determine whether IL-1beta could directly stimulate ACTH secretion from perifused equine anterior pituitary cells, and whether CRH pre-incubation affected corticotroph responsiveness. Isolated equine anterior pituitary cells were pre-incubated with media containing 10 nM CRH or vehicle for 20 hours before being loaded onto columns and perifused with 0.02 nM CRH and 100 nM cortisol. Columns were given a 5-minute pulse of arginine vasopressin (AVP, 10 nM), perifused for 4 hours with 0 (control) or 1 nM IL-1beta, then given a further 5-minute pulse of AVP (10nM). ACTH was measured in 5 minute fractions. In the setting of CRH pre-incubation, cells perifused with IL-1beta for 4 hours showed increased basal ACTH secretion compared to control (114 +/- 6 pM vs. 86 +/- 4 pM [means +/- S.E.M.], p < 0.001) and a significantly greater ACTH response to the final AVP pulse (240 +/- 32% vs. 96 +/- 30%, p = 0.009, expressed as % of ACTH response to the initial AVP pulse). The potentiation of AVP-stimulated ACTH release by IL-1 was not observed in cells pre-incubated with vehicle alone. In conclusion, IL-1 increases ACTH release in equine corticotroph cells pre-incubated with CRH and potentiates responsivity to AVP.     

Further evaluation of IGF-I responsiveness to ACTH in children affected with IGHD.

In our previous studies we had demonstrated that, in children affected with isolated GH deficiency (IGHD), a short-term recombinant growth hormone (rGH) therapy increases the 11-deoxycortisol (S) secretion and induces an IGF-I responsiveness to the ACTH challenge. The aim of the present study was to further investigate the mechanisms by which IGF-I is secreted after ACTH challenge in children affected with IGHD by correlating IGF-I versus cortisol (F) time courses after ACTH administration. Ten children affected with IGHD were subjected to rGH therapy (4 IU/day subcutaneously) for 10 days. The responsiveness of IGF-I, F and S to the ACTH 1-17 test were evaluated before and at the end of the therapy. No IGF-I response to the ACTH test was recorded in the patients before the rGH treatment, whereas after rGH administration ACTH induced a significant IGF-I release (p < 0.001) which started at the 1st hour, reached a peak value between the 5th and 6th hours and disappeared at the 10th hour. In conclusion, our study confirms that a short-term rGH therapy induces an IGF-I responsiveness to ACTH and helps to better define the kinetics and the mechanism of this IGF-I response to ACTH.     

Monensin inhibition of corticotropin releasing factor mediated ACTH release

Monensin is a sodium selective carboxylic ionophore that has been helpful in studying the intracellular mechanisms of protein secretion by its ability to inhibit transport of secretory proteins, particularly through the Golgi apparatus, and by its capacity to block intracellular posttranslational processing events. We studied in rat anterior pituitary cell culture the effects of monensin on: CRF stimulated ACTH release; presynthesized (stored) ACTH release; and on forskolin- (activator of adenylate cyclase) and KCl- (a membrane depolarizer which does not stimulate ACTH synthesis) induced ACTH release. Monensin inhibited CRF stimulated ACTH release in a dose-dependent fashion. The ED50 was 2.7 x 10(-8) M and maximal inhibition was 52% at 1.5 x 10(-7) M. Inhibition at 40 minutes of CRF incubation was similar to the percent inhibition noted at 1 hr 40 min and 2 hr 40 min. Monensin (1.5 x 10(-6) M) decreased the amount of ACTH release from cells incubated with cycloheximide plus CRF by 32% (p less than 0.01). Monensin individually inhibited forskolin (2 x 10(-6) M) and dibutyryl cyclic AMP (3 x 10(-3) M) mediated ACTH release in a dose-dependent fashion. The inhibition of forskolin and dibutyryl cyclic AMP mediated ACTH release by 1.5 x 10(-6) M monensin was 48% and 46% respectively. Monensin (1.5 x 10(-6) M) also reduced KCl (50 mM) stimulated ACTH release by 48%. This study demonstrates that monensin inhibits CRF mediated ACTH release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ectopic ACTH syndrome

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4–6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.     

Influence of cholecystokinin on hypothalamic-stalk median-eminence-extract stimulation of ACTH output from isolated pituitary cells

The influence of cholecystokinin 33 (CCK33) on CRF-like stimulation of ACTH output was tested in vitro using isolated pituitary cells. ACTH was assayed using isolated adrenal cell preparations. The CRF-like material was contained in a crude acetic-acid extract of hypothalamic stalk median eminence (HSME). CCK33, in doses of 1 U, 10(-3) U, and 10(-6) U/ml cell suspension had no influence on basal or ACTH-stimulated corticosterone output from isolated adrenal cells. Isolated pituitary cells responded in a dose-related fashion of HSME extract, however, the absolute response to a given dose of HSME extract varied according to the basal (non-stimulated) output of a particular cell preparation. CCK33, in the dose range tested, had no influence on basal ACTH output. In contrast, 10(-3) U/ml oc CCK33, which corresponds to a concentration of 8 X 10(-11) M, significantly inhibited the output of ACTH from isolated pituitary cells stimulated by 0.2 equivalents of HSME. Higher concentrations of CCK33 had a variable effect. We conclude that cholecystokinin may have a role in the regulation of HSME-stimulated ACTH output from the pituitary.     

Validation of a single-compartment approach to the calculation of secretion rates of ACTH.

A single-compartment model used in this laboratory for continuously calculating ACTH secretion rates from measured plasma ACTH concentrations has been tested for its ability to follow changing rates of ACTH entry (rapid departure from steady state). ACTH was infused at known moderately high but physiological rates into anaesthetized dogs (Nembutal). Under such conditions endogenous secretion is initially less than 5% of infused rates. Orthogonal polynomials (ACTHt) were fitted to plasma ACTH vs. time data. Then secretion ratet = (ACTHt X MCR) + (dACTHt/dt X V) where it was previously shown that the metabolic clearance rate of ACTH (MCR) lacked significant inter-animal or concentration-dependent variation, and its distribution volume (V) was also constant. The calculated ACTH entry rate curves (a) followed a 10-fold increase in infusion rate over 4 min and subsequent rapid decline with a lag of only about 1 min and, despite some blurring, gave an integrated response equal to 94 +/- 5.5% of the known signal, and (b) followed a sinusoidal change in infusion rate (amplitude, 1.7 X base rate; period, 40 min) with a few percent error and negligible lag. These signals imitate (a) an abrupt stress response, and (b) other rapid departures from steady state.     

C-terminal fragments of ACTH stimulate feeding in fasted rats.

Peptides derived from pro-opiomelanocortin, including alpha-MSH and ACTH, play important roles in the regulation of feeding. We investigated the central effect of ACTH 1-39 (ACTH) and peptides derived from the N-terminus (ACTH 1-10, Acetyl-ACTH 1-13-amide [alpha-MSH]) and C-terminus (ACTH 18-39 and ACTH 22-39) of this peptide on feeding in 16 hour-fasted or rats fed ad libitum. As expected, ACTH reduced feeding in fed and previously fasted rats, although this anorectic effect was more pronounced in fasted rats. The N-terminal-derived peptide alpha-MSH, but not ACTH 1-10, reduced cumulative food intake over 2 h after its injection intracerebroventricularly (icv) in 16 h-fasted, but not in fed rats. In contrast, the C-terminal fragments produced a long-lasting increase in feeding in fasted, but not in fed rats. The anorectic effects of N-terminal fragments of ACTH are recognised to be mediated via melanocortin MC4 receptors. However, the orexigenic effects of the C-terminal fragments do not appear to be conducted via MC4 receptors, since neither ACTH 18-39 nor ACTH 22-39 stimulated cAMP accumulation nor inhibited the ACTH-stimulated cAMP accumulation in HEK-293 cells transfected with the recombinant MC4 receptor.     

Effects of ACTH on plasma levels of adrenal steroids in essential hypertension.

Plasma concentrations of progesterone (P), deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OH P), corticosterone (B), deoxycortisol (S), cortisol (F) and aldosterone (A) in 8 control subjects (mean age: 40.5 years) and 10 patients with essential hypertension (EH) (mean age: 48.5 years) were determined before, 4 and 8 hours after an infusion of ACTH at a rate of 25 units per 8 hours. Secretion rates (SR) of 18-hydroxy-11-deoxycorticosterone (18-OH DOC) were measured 24 hours before and again on the day of ACTH infusion. All subjects were studied on the fourth day of a diet containing 135 mEq of sodium and 90 mEq of potassium. There was no statistically significant difference between 8 control subjects and 10 patients with EH in the 7 plasma steroid levels and the SR of 18-OH DOC before ACTH infusion. The mean plasma P response to ACTH was slightly lower in controls than in patients with EH, while that of 17-OH P (in male subjects) was slightly higher. The mean plasma B response was significantly lower after 4 hours of ACTH infusion (p less than 0.01), while that of DOC was significantly higher after 8 hours of ACTH infusion (p less than 0.05) in patients with EH. The mean plasma S rose significantly more in patients with EH (p less than 0.025) at 4 and 8 hours after ACTH infusion. The mean plasma F response to ACTH infusion was slightly lower in patients with EH than in controls. The mean response of 18-OH DOC SR to ACTH infusion was slightly higher in patients with EH than in controls. The mean plasma A response was significantly higher in patients with EH than in controls 4 (p less than 0.05) and 8 hour (p less than 0.001) after an ACTH infusion. These results could be explained in part by abnormalities in the 17- and 11-hydroxylase systems, and that the abnormality in 11-hydroxylation was more pronounced than that in the 17-position. Furthermore, we suspect that the sensitivity of adrenal aldosterone to ACTH might be increased or another accelerated pathway to aldosterone biosynthesis might exist in patients with EH.     

Hormonal responses of lactating dairy cattle to TRH and ACTH in a shade management system within a subtropical environment

Lactating cows (64) were balanced by breed (54 Holstein and 10 Jersey) and assigned randomly to shade (S) or no shade (NS) management treatments for a continuous 20 wk trial beginning 5-5-76. A sub-sample of Holstein cows, five S and five NS, were fitted with jugular catheters 84 days after initiation of experiment. Thyrotropin Releasing Hormone (TRH; 100 mug) was administered intravenously at 1200 h to evaluate prolactin responses. Two days later each cow received intravenously 200 IU of ACTH at 1100 h to compare acute corticoid responses to ACTH. Mean prolactin response to TRH was greater for NS cows (291 vs 169 ng/ml; P < .01) as was peak plasma concentrations at 20 min (467 vs 267 ng/ml; P < .01). Mean corticoid response to ACTH injection was less for NS cows (52 vs 70 ng/ml; P < .10). Corticoid concentrations of plasma in both treatments had declined 65% by 7 h postinjection. These endocrine differences may be associated with thermoregulation and/or metabolic adjustments of cows exposed to different environmental systems of management during a seasonal period of thermal stress.