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PubMed1988

Dose-response relationships between plasma adrenocorticotropin (ACTH), cortisol, aldosterone, and 18-hydroxycorticosterone after injection of ACTH-(1-39) or human corticotropin-releasing hormone in man.

The effects of sc injections (at 1500 h) of increasing amounts of synthetic human ACTH-(1-39) (1.25-30 micrograms) on plasma ACTH, cortisol, aldosterone, and 18-hydroxycorticosterone were compared with those of iv injections of 30 and 100 micrograms synthetic human CRH in nine normal men. Five micrograms of ACTH, sc, was the lowest dose that significantly increased plasma levels of the three steroids. CRH (30 micrograms, iv) increased plasma cortisol and 18-hydroxycorticosterone, but not aldosterone, while 100 micrograms CRH also raised aldosterone secretion. The dose-response curve (peak plasma ACTH level vs. maximum increment of plasma cortisol within the first hour) was initially very steep. Plasma ACTH levels between 50 and 60 ng/L (11-13 pmol/L) stimulated cortisol to almost 80% of the maximal increment obtained with plasma ACTH levels above 300 ng/L (greater than 66 pmol/L). This dose-response relationship is similar to that found in clinical tests of the pituitary-adrenal axis (insulin test, metyrapone test). The effects of plasma ACTH released by CRH on cortisol secretion were not significantly different from those of injected ACTH. Our results argue against the hypothesis that the effect of CRH on steroid secretion is mediated or modulated by POMC-derived peptides other than ACTH.

18-Hydroxycorticosterone↗
PubMed1989

Failure of bronchial lavage to detect elevated levels of adrenocorticotropin (ACTH) in patients with ACTH-producing bronchial carcinoids.

Saline lavage of the major bronchial segments was performed in five patients immediately preceding lobectomy to remove an ACTH-producing bronchial carcinoid. Lavage fluid from each bronchus was concentrated, and ACTH determinations were performed. Elevated concentrations of ACTH were not demonstrated in the aspirate from the bronchus containing the known tumor. Two additional patients with ectopic ACTH syndrome from an unknown primary source also underwent selective segmental bronchial lavage for ACTH determination. Neither patient demonstrated ACTH gradients in the lavage specimens. One was found to have an ACTH-producing bronchial carcinoid 18 months after negative lavage. Selective segmental bronchoscopic lavage with measurement of ACTH levels on the aspirate is not an effective technique for detecting ACTH-producing bronchial carcinoid tumor.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

ACTH induces c-fos proto-oncogene in fibroblasts expressing the ACTH receptor.

The entire ACTH receptor (ACTH-R) cDNA was amplified by RT/PCR from mouse Y-1 adrenocortical cells, subcloned into the pMOSBlue T vector, sequenced and inserted into the pSVK3 mammalian vector to obtain pSVACTHR. Balb 3T3 fibroblasts were co-transfected with pSVACTHR plus pSV2-neo and the transfectants were selected with G418 and cloned. Genomic integration of pSVACTHR and transcription of ACTH-R cDNA were checked by Southern blot and RT/PCR respectively. Expression of active ACTH-R protein was tested by measuring cAMP production in response to ACTH. Two ACTH-R expressing transfectants (clones 03 and 07) increased cAMP accumulation in response to ACTH. They were morphologically identical to parental 3T3 cells, but required 10-20% FCS to grow. In these transfectants, ACTH induced c-FOS protein expression, but did not activate the ERK isoforms of MAP Kinase and did not stimulate DNA synthesis. Apparently, the ACTH-R in Balb 3T3 cells induces the c-fos gene by a pathway independent of cAMP/protein kinase A and ERK/MAP Kinase.

3T3 Cells↗
PubMed1985

Characteristics of angiotensin II-, K+- and ACTH-induced calcium influx in adrenal glomerulosa cells. Evidence that angiotensin II, K+, and ACTH may open a common calcium channel.

The characteristics of angiotensin II-, K+-, and adrenocorticotropin (ACTH)-induced calcium influx were studied in isolated adrenal glomerulosa cells. Basal calcium influx rate is 0.64 +/- 0.09 nmol/min/mg of protein. Addition of angiotensin II (1 nM) causes a rapid 230% increase in calcium influx rate. This angiotensin II-induced calcium influx is sustained and is rapidly reversed by angiotensin II antagonist, [Sar1,Ala8]angiotensin II. Addition of either K+ or ACTH (1 nM) causes a 340 or 160% increase, respectively, in the rate of calcium influx. The effect of either angiotensin II, K+, or ACTH on calcium influx is dependent on extracellular calcium. The apparent Km for calcium is 0.46, 0.35, and 0.32 mM, respectively. When the extracellular concentration of K+ is 2 mM, neither angiotensin II nor ACTH stimulates calcium influx. Conversely, when extracellular K+ is increased to 6 mM, both angiotensin II and ACTH cause a greater stimulation of calcium influx than at 4 mM K+. When extracellular K+ is increased to 10 mM, calcium influx is 360% of the basal influx seen at 4 mM K+, and neither angiotensin II nor ACTH further stimulates the influx rate. Nitrendipine (1 microM) blocks both angiotensin II- and K+-induced calcium influx completely. In contrast, 10 microM nitrendipine does not completely block ACTH-induced calcium influx. The calcium channel agonist, BAY K 8644, also stimulates calcium influx; 10 nM BAY K 8644 leads to a rate of calcium influx which is 185% of basal. This BAY K 8644-induced increase in calcium influx and that caused by either angiotensin II or ACTH are additive. In contrast, BAY K 8644 has more than an additive effect on the calcium influx when paired with 6 mM K+. These results suggest that angiotensin II, K+, and ACTH stimulate calcium influx via a common calcium channel but act by different mechanisms to alter its function.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing's syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion.

The role of desmopressin, alone or in combination with CRH, in the differential diagnosis between Cushing's disease (CD) and ectopic ACTH secretion (EAS) still remains uncertain. Based on existing data, the desmopressin test is regarded as an alternative to the CRH stimulation test and, when given in combination with CRH, it has been suggested to completely discriminate between patients with CD and EAS. However, assessment of these tests has been limited in only a small number of patients with EAS. Desmopressin is a relatively specific V2 vasopressin receptor (V2R) agonist. Although expression of V3 vasopressin receptor (V3R) is common in tumors with EAS, the expression of V2R has not been extensively investigated. In the present study, we report our findings of the desmopressin and the combined CRH-desmopressin test in a series of patients with CD and EAS; also, the expression of V2R and V3R was investigated in tumors with EAS by a RT-PCR method. We assessed a cohort of 31 patients with ACTH-dependent Cushing's syndrome, including 26 patients with CD and five cases with histologically confirmed EAS. To avoid bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1-specificity at each level of the percent cortisol (F) and ACTH responses to these tests. Following desmopressin administration there was an overlap of the percent F and ACTH responses among patients with CD and EAS, and the area under the ROC curve for both these responses was not significantly different than that occurring by chance. This was also true for the percent F response following the combined CRH-desmopressin test. However, the area under the ROC curve for the percent ACTH rise following the combined test was significantly different; the point of the ROC curve closest to 1 corresponded to a percent ACTH rise of 218% (88% sensitivity and 80% specificity). Expression of V2R and V3R mRNA was investigated in four of the five excised tumors with EAS and revealed the presence of the V2R in all, whereas the V3R mRNA was expressed in three of these cases. In conclusion, in this series the desmopressin test produced a significant overlap of responses between CD and patients with EAS and, therefore, is of limited value in the differential diagnosis of the ACTH-dependent Cushing's syndrome. This is most probably due to the expression of the V2R in tumors with EAS. Moreover, following the combined CRH-desmopressin test only the ACTH but not the F responses were diagnostically useful, but still far from completely discriminating patients with CD and EAS.

ACTH Syndrome, Ectopic↗
PubMed1981

Selective venous sampling for ACTH in Cushing's syndrome: differentiation between Cushing disease and the ectopic ACTH syndrome.

We performed selective venous catheterization and sampling for ACTH in six patients with ACTH-secreting pituitary adenomas (Cushing's disease) and four patients with occult ectopic ACTH-secreting neoplasms. In five patients with Cushing's disease in whom the inferior petrosal sinus could be catheterized, ACTH levels were unequivocally higher than simultaneous peripheral values: The ratio was greater than 2.0, with a range of 2.2 to 16.7. In contrast, the inferior petrosal sinus-to-peripheral ACTH ratio in three patients with ectopic ACTH secretion was less than 1.5. In the fourth patient, an arteriovenous gradient of 6.8 was shown 2 years before a bronchial carcinoid tumor was clinically apparent. Central-to-peripheral ACTH ratios at the level of the jugular bulb and jugular vein were not diagnostic. We conclude that selective venous ACTH sampling from the inferior petrosal sinus is a reliable and useful aid in the differential diagnosis of Cushing's syndrome when standard clinical and biochemical studies are inconclusive.

ACTH Syndrome, Ectopic↗
PubMed2006

The effect of centrally administered ghrelin on pituitary ACTH cells and circulating ACTH and corticosterone in rats.

Ghrelin is a brain-gut peptide known for its growth hormone (GH)-releasing and appetite-inducing activities. This natural GH secretagogue (GHS) was originally purified from rat stomach, but it is expressed widely in different tissues where it may have endocrine and paracrine effects. The central effects of ghrelin on adrenocorticotropic hormone (ACTH) cells, ACTH release and subsequent corticosterone release from adrenal glands remains to be clarified. The aim of this study was to specifically determine the morphological features of ACTH-producing pituicytes and blood concentration of ACTH and corticosterone after central administration of ghrelin. Five doses of rat ghrelin or PBS (n=10 per group) were injected every 24 h (1 microg of ghrelin in 5 muL PBS), into the lateral cerebral ventricle of male rats. Results showed that ghrelin increased (p<0.05) absolute and relative pituitary weights compared to controls (58% and 41% respectively). Morphometric parameters, i.e. the volume of the ACTH cells, nuclear volume, and volume density were all increased (p<0.05), by 17%, 6% and 13%, respectively, 2 h after the last ghrelin treatment. Ghrelin increased circulating concentrations of ACTH and corticosterone (p<0.05) by 62% and 66%, respectively. The data provide clear documentation that intracerebroventricular ghrelin stimulates ACTH cell hypertrophy and proliferation, and promotes ACTH and corticosterone release. Determining the role of ghrelin in physiological stress responses and whether control of the peptide's activity would be useful for prevention and/or treatment of stress-induced diseases remain important research goals.

Adrenocorticotropic Hormone↗
PubMed1986

Suppressed pituitary ACTH response after ACTH treatment of infantile spasms.

Suppression of an adrenocorticotropic hormone (ACTH) response to insulin hypoglycemia has been reported in ACTH-treated adults. There are no guidelines for withdrawal of ACTH treatment in children. After observing suppressed morning cortisol in several children, insulin tolerance tests were performed in five children within 48 hours after tapered withdrawal of ACTH treatment for myoclonic seizures. ACTH response, as determined by cortisol and beta-endorphin radioimmunoassay, was adequate in four of the children. One child showed low basal levels and minimal elevation during hypoglycemia for both beta-endorphin (0 to 3 pg/ml) and cortisol (3.6 to 4.4 micrograms/dL) on initial testing, but normal responses six weeks later. Measurement of beta-endorphin response supported a central basis for suppression in the child, who had had an adrenal hemorrhage during gram-negative sepsis while on ACTH. ACTH release is transiently suppressed in some children after exogenous ACTH treatment. Tapered withdrawal and stress coverage is recommended.

Adrenocorticotropic Hormone↗
PubMed1992

Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone.

The rapid ACTH injection test is an indirect screening test for adrenocortical insufficiency. As a supplement to this test, we evaluated the practicability of single measurements of plasma cortisol, ACTH, aldosterone, and PRA as a definitive diagnostic test of primary adrenocortical insufficiency (PAI). We also tested the value of PRA measurements during treatment with hydro- and fludrocortisone (HC and FC) as a guide for correct mineralocorticoid substitution. In 45 patients with PAI, results of the rapid ACTH test and single measurements of the four hormones (all tests between 0800-0900 h) were compared. Single hormone measurements were also made in 55 normal subjects and 46 patients with pituitary disease (cortisol and ACTH only), most of them with mild to severe secondary adrenocortical insufficiency (SAI). The rapid ACTH test was abnormal in 100% of 41 patients with PAI tested. Plasma ACTH, PRA, and the ratios of ACTH/cortisol and PRA/plasma or urinary aldosterone were clearly elevated in 100% of the patients with PAI. The ACTH/cortisol ratio also distinguished 100% of patients with PAI from those with SAI, but not always control subjects from those with SAI. Thus, dynamic tests (CRH or insulin tests) are indicated if SAI is suspected. PAI and involvement of zona fasciculata and glomerulosa function can be diagnosed with high reliability by measuring cortisol, ACTH, aldosterone, and PRA either together with the rapid ACTH test or later, after a short interval of steroid substitution. PRA measurements during treatment with HC and FC correlated better with the mineralocorticoid dose than plasma potassium and sodium levels. PRA measurement is a valuable guide for FC replacement therapy. It should be titrated into the upper normal range to avoid under- and overtreatment.

Addison Disease↗
PubMed1981

[Studies on immunoreactive ACTH from human term placenta. (I) Detection of a high molecular weight-immunoreactive ACTH in term placenta (author's transl)].

Extracts of human term placenta were fractionated by Sephadex G-75 gel filtration and assayed for immunoreactive ACTH. Both high and low molecular weight protein fractions were detected to be immunologically reactive toward anti-human ACTH (1--39 alpha) antibody. For the extraction of low molecular weight ACTH from human term placenta (pl. -ACTH), a glacial acetic acid-acetone mixture was employed, while a pH 3.0-HCl solution was used for high molecular weight immunoreactive ACTH. The high molecular weight immunoreactive ACTH fraction (F-I), co-eluted with horse hemoglobin from a Sephadex G-75.column in 0.1M acetic acid, was essentially devoid of low molecular weight materials as revealed by polyacrylamide gel disc electrophoresis at pHs 9.5 and 4.3. Tryptic digestion of F-1 at pH 8.1 and 37 degrees C for 4 hr with E/S of 1/100, followed by fractionation with a Sephadex G-75, resulted in the formation of lower molecular weight fragments. One fragment was eluted at the same position as that of porcine ACTH with a recovery of 86% of immunoreactivity of F-I. Another fragment which was eluted last exhibited positive beta-endorphin receptor binding activity. These results suggest the presence of a common precursor protein to ACTH and beta-endorphin in human term placenta.

Adrenocorticotropic Hormone↗
PubMed1997

One microgram is the lowest ACTH dose to cause a maximal cortisol response. There is no diurnal variation of cortisol response to submaximal ACTH stimulation.

There are many suggestions in the literature that the adrenal gland is more sensitive to ACTH in the evening than in the morning. However, all these studies in humans were conducted when the basal cortisol level was not suppressed, and were based on the observation that, after stimulation, the increases in cortisol differed, though the peak values were the same. To examine this, we established the lowest ACTH dose that caused a maximal cortisol stimulation even when the basal cortisol was suppressed, and used a smaller dose of ACTH for morning and evening stimulation. The lowest ACTH dose to achieve maximal stimulation was found to be 1.0 microgram, with which dose cortisol concentration increased to 607.2 +/- 182 nmol/l, compared with 612.7 +/- 140.8 nmol/l with the 250 micrograms test (P > 0.3). The use of smaller doses of ACTH (0.8 and 0.6 microgram) achieved significantly lower cortisol responses (312 +/- 179.4 and 323 +/- 157.3 nmol/l respectively; both P < 0.01 compared with the 1 microgram test). When a submaximal ACTH dose (0.6 microgram) was used to stimulate the adrenal at 0800 and 1600 h, after pretreatment with dexamethasone, no difference in response was noted at either 15 min (372.6 +/- 116 compared with 394.7 +/- 129.7 nmol/l) or 30 min (397.4 +/- 176.6 compared with 403 +/- 226.3 nmol/l; P > 0.3 for both times). These results show that 1.0 microgram ACTH, used latterly as a low-dose test, is very potent in stimulating the adrenal, even when baseline cortisol is suppressed; smaller doses cause reduction of this potency. Our data show that there is probably no diurnal variation in the response of the adrenal to ACTH, if one eliminates the influence of the basal cortisol level and uses physiologic rather than superphysiologic stimuli.

Adrenocorticotropic Hormone↗
PubMed1994

Effects of short- and long-term administration of phenobarbital on endogenous ACTH concentration and results of ACTH stimulation tests in dogs.

The effects of short-term phenobarbital administration were evaluated in 6 adult mixed-breed dogs that received phenobarbital (5 mg/kg of body weight, PO, q 12 h) for 8 consecutive weeks. Six additional dogs served as untreated controls. At 2-week intervals, endogenous adrenocorticotropic hormone (ACTH) concentration and cortisol concentration before and 2 hours after administration of porcine aqueous ACTH (2.2 IU/kg, IM) were measured. By means of one-way ANOVA, we were not able to detect a significant (P > or = 0.05) difference in endogenous ACTH concentration and cortisol concentration before and after exogenous ACTH administration within groups over time or between groups at any time. To evaluate effects of long-term phenobarbital administration, sera and plasma were collected from 5 epileptic dogs that had received phenobarbital for > 2 years and had serum phenobarbital concentrations > 20 micrograms/dl. Endogenous ACTH concentration and cortisol concentration, before and after administration of ACTH, were within established reference ranges for all 5 dogs. Together, these results suggest that phenobarbital administration alone does not affect endogenous ACTH concentration or response to exogenous ACTH administration in dogs, and that these may be valid screening tests for hyperadrenocorticism in most dogs receiving phenobarbital.

Adrenocorticotropic Hormone↗
PubMed1997

Effect of desmopressin on ACTH and cortisol secretion in states of ACTH excess.

OBJECTIVE: To assess the ability of desmopressin administration to stimulate ACTH/cortisol secretion in patients with Cushing's disease, either before or after surgery, and in patients with other states characterized by ACTH hypersecretion, and to compare the results with those obtained after CRH testing. DESIGN AND SUBJECTS: Plasma ACTH and serum cortisol levels were evaluated after the administration of desmopressin (10 micrograms i.v.), CRH (1 microgram/kg i.v.) and saline on different days in 17 patients with Cushing's disease, 1 with occult ectopic ACTH syndrome, 5 with Addison's disease, 3 who had been bilaterally adrenalectomized for Cushing's syndrome and 4 normal subjects. After pituitary adenomectomy desmopressin and CRH were administered again to 13 of the patients who had undergone pituitary surgery for their Cushing's disease. RESULTS: In 16 patients with Cushing's disease with microadenoma a positive ACTH/cortisol rise occurred in 11 patients after both desmopressin and CRH, 2 other patients were responsive only to desmopressin and 2 only to CRH, while in 1 patient equivocal responses to both tests were found. The persistence of a hormonal response to desmopressin after pituitary adenomectomy for Cushing's disease correlated with unsuccessful surgery, while, contrary to CRH, absent ACTH/cortisol rises were found in cured patients 1 and 12 months after operation. In 1 patient suspected for ectopic ACTH hypersecretion, desmopressin and CRH administration did not cause any ACTH/cortisol rise. Significant ACTH rises occurred after both desmopressin and CRH testing in patients with Addison's disease. All the 3 patients adrenalectomized for Cushing's syndrome showed a rise of ACTH levels after CRH, while a similar response after desmopressin occurred in only one of them. CONCLUSIONS: Desmopressin is able to stimulate ACTH and hence cortisol release in Cushing's disease. It may be a useful test in patients with doubtful responses to CRH test, in those exhibiting responses to CRH indistinguishable from those of normal subjects and in the postoperative follow-up of Cushing's disease. In some patients with abolished or reduced cortisol feed-back at hypothalamic-pituitary level the sensitivity of normal corticotrophs to desmopressin is enhanced.

ACTH Syndrome, Ectopic↗
PubMed1995

Effects of ACTH and ACTH 4-10 on aversive memory retrieval in rats.

The aim of the study was to examine whether ACTH and ACTH-fragment 4-10, given before the test would produce a selectively enhanced retrieval of aversive memories, in the same way as preexposure to inescapable footshocks, in rats. For this purpose animals conditioned in a T-maze with appetitive (10% sucrose) and aversive (2.0 mA footshock) events were administered (s.c.) a single dose of 10, 20 or 40 ug/rat of ACTH or 5, 10 or 20 ug/rat of ACTH-fragment 4-10, 20-min before testing. The retention test conducted in the same training apparatus 72-hrs after conditioning showed a dose-dependent increase in latencies to enter the previously shocked goalarm with the absence of such a difference in responding to the nonshocked goalarm, in ACTH and ACTH 4-10 treated groups. This differential response was not observed in saline treated rats. This effect of peptides on memory retrieval was similar to that seen following inescapable footshock in rats. The results suggest the possible involvement of ACTH in the differential enhancement of memory of helplessness condition.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Positive inotropic effects of an ACTH analogue (ACTH 1-17) on myocardial performance.

The aim of the present investigation was to study the effects of a single 100-micrograms i.v. administration of the synthetic heptadecapeptide [beta-Ala1-Lys17]ACTH1-17-4-amino-N-butylamide (ACTH 1-17) on the left ventricular performance. The systolic time intervals (STI) were recorded in 20 healthy adult young subjects (10 treated with ACTH 1-17 and 10 receiving placebo) before as well as 20, 40, 60 and 80 min after the i.v. ACTH 1-17 or placebo infusion. The STI were recorded immediately after blood withdrawal for measuring cortisol, aldosterone, adrenaline and noradrenaline plasma levels. A highly significant statistical difference was demonstrated for preejection period (PEP) and preejection period/left ventricular ejection time (PEP/LVET) ratio between subjects treated with ACTH 1-17 and subjects receiving placebo. As expected, a significant increase of cortisol and aldosterone plasma levels was observed in subjects treated with ACTH 1-17. The difference of adrenaline and noradrenaline plasma levels was statistically highly significant between subjects treated with ACTH 1-17 and those receiving placebo. The lack of increase in PEP and PEP/LVET ratio recorded in subjects treated with ACTH 1-17 is consistent with an increased left ventricular contractile performance. An increased plasma catecholamine release is postulated as the mechanism of this improvement.

Adrenocorticotropic Hormone↗
PubMed1983

Effect of ACTH, epinephrine, beta-endorphin, naloxone, and of the combination of naloxone or beta-endorphin with ACTH or epinephrine on memory consolidation.

The effect on retention of the post-training intraperitoneal administration of ACTH1-24 (0.2 or 2.0 micrograms/kg), epinephrine HCl (5.0 or 50.0 micrograms/kg), human beta-endorphin (0.1 or 1.0 microgram/kg), naloxone (0.4 mg/kg), and of the combination of naloxone or beta-endorphin with ACTH or epinephrine was studied in two different but closely related step-down inhibitory avoidance tasks in rats: task 1 (5 cm high 25 X 25 cm platform; 0.5 mA continuous footshock) and task 2 (7 X 25 cm platform, 0.3 mA discontinuous footshock). In task 1, saline control animals showed good retention in a test session carried out 24 hr later; beta-endorphin, ACTH and epinephrine caused amnesia; beta-endorphin potentiated the amnesic effect of ACTH and epinephrine; and naloxone caused memory facilitation and reversed the amnesic effect of ACTH and epinephrine. In task 2, control animals showed poor retention; beta-endorphin caused amnesia at the dose of 0.1 but not 1.0 microgram/kg; the other three drugs caused memory facilitation; naloxone potentiated the facilitatory effect of ACTH and epinephrine; and beta-endorphin reversed it and transformed it into a deep amnesia. These findings suggest that an opioid-mediated amnesic mechanism modulates the effect of ACTH and epinephrine on memory consolidation, either by dampening that effect when training parameters tend to make it facilitatory, or by enhancing it when training conditions tend to make it amnesic. On the basis of these and previous data it seems likely that the amnesic effect of ACTH and epinephrine could be mediated by endogenous beta-endorphin release.

Adrenocorticotropic Hormone↗
PubMed1985

Effects of high-dose and low-dose naloxone on plasma ACTH in patients with ACTH hypersecretion.

The effect of a high (5.4 mg/h) and a low (0.8 mg/h) dose of naloxone (i.v. over a period of 90 min) on ACTH secretion was compared with placebo in patients with Addison's disease, congenital adrenal hyperplasia, Cushing's disease or Nelson's syndrome. In seven patients with primary adrenal insufficiency the high dose of naloxone provoked a significant increase of plasma ACTH concentrations (P less than 0.02) whereas the low dose of naloxone failed to influence ACTH secretion. In six patients with ACTH dependent Cushing's disease or Nelson's syndrome both doses failed to alter plasma ACTH levels. These results support the concept of inhibitory delta- or kappa-opiate receptors in the regulation of ACTH secretion. In patients with Cushing's disease or Nelson's syndrome ACTH secretion is insensitive to naloxone, presumably because of an autonomous pituitary adenoma or hypothalamic derangement.

Adrenal Gland Diseases↗
PubMed1979

Evaluation of receptor function in ACTH-responsive and ACTH-insensitive adrenal tumor cells.

Two variant cell lines (Y6 and OS3), derived from the ACTH-sensitive mouse adrenocortical tumor clone Y1, are defective in the ACTH-sensitive adenylate cyclase system. This study further characterizes the nature of the defects in Y6 and OS3 cells using ACTH1-10, ACTH4-10, and cholera toxin. In Y1 cells, ACTH1-39, ACTH1-10, and ACTH4-10 stimulated steroidogenesis to the same maximum level with Kd' values of 5 x 10(-11) M, 5 x 10(-7) M and 10(-4) m respectively. ACTH1-10 (0.4 mM) and ACTH4-10 (3.2 mM) increased the accumulation of adenosine 3',5'-monophosphate (cAMP) in Y1 cells two- to three-fold. Cholera toxin increased steroidogenesis and cAMP accumulation in Y1 cells with Kd' values of 0.4 ng/mL and 9 ng/mL respectively. Y6 and OS3 cells responded to added cholera toxin with increased cAMP accumulation and increased steroidogenesis but did not respond to ACTH1-39, ACTH1-10, or ACTH4-10 at concentrations effective in Y1 cells. These data are interpreted to suggest that Y6 and OS3 cells are defective in a process or component that links the principal binding regions of the ACTH receptor to the catalytic subunit of the adenylate cyclase system. Attempts to were made to assess the interactions of ACTH with the principal binding regions of the ACTH receptor by analysis of binding of radioactive, iodinated ACTH1-24. ACTH binding, however, showed low affinity, high capacity, and no target-tissue specificity, and was considered not to be useful in evaluating the integrity of the ACTH receptor.

Adenylyl Cyclases↗