Increased Plasma ACTH Concentrations Research Articles

Hypoglycemia Enhances Turnover of Corticotropin-Releasing Factor and of Vasopressin in the Zona Externa of the Rat Median Eminence*

Insulin administration to overnight fasted rats causes a dose-dependent decline in plasma glucose concentrations and a dose-dependent increase in plasma ACTH concentrations. The ACTH response, but not the glucose response, was blocked by treatment with chlorpromazine-morphine-pentobarbital, indicating that the main factors triggering the ACTH response are of central, rather than peripheral, origin. To study whether insulin affected the turnover of CRF and vasopressin (AVP) in the zona externa of the median eminence (ZEME), we determined the rate of decline of both hypophysiotropic factors in rats with or without blockade of axonal transport by colchicine. In the ZEME, the concentrations of CRF and AVP were assessed by quantitative immunocytochemistry (QICC) in tissue sections or by RIA in median eminence extracts. QICC allows selective quantification of AVP and other peptides within the ZEME. The changes in the CRF content, as measured by QICC and RIA, were linearly correlated (r = 0.99), demonstrating that changes in peptide-staining intensity reflect changes in peptide content. Colchicine, when given intracisternally in a nontoxic dose of 5 micrograms, had no marked effect on resting plasma levels of ACTH and only slightly reduced the ACTH response to insulin-induced hypoglycemia. In the ZEME, CRF and AVP concentrations at rest were not affected by colchicine. In colchicine-treated rats insulin-induced hypoglycemia resulted in a prominent decline in CRF and AVP concentrations in the ZEME. The CRF concentration declined at a rate of 23%/h over a period of 3 h. The AVP concentration declined to a similar extent as CRF over the first hour, but tended to fall at the later time points. We conclude that hypoglycemia increases turnover of both CRF and AVP in the ZEME. However, the turnover rates of both hypophysiotropic peptides do not appear to be quantitatively coupled.

Corticotropin-releasing activity of gastrin-releasing peptide in normal men.

Gastrin-releasing peptide (GRP; mammalian bombesin) exerts several functions within the hypothalamus and is a putative regulator of pituitary hormone secretion. We investigated the effect of GRP on the secretion of pituitary hormones and cortisol in normal men. GRP was infused iv as primed infusions of 0.12 pmol/kg BW. min for 30 min (GRP I) and 1.50 pmol/kg. min for an additional 30 min (GRP II). GRP dose-dependently stimulated ACTH secretion compared with the effect of saline [net change in ACTH (delta ACTH) before and after treatment: GRP I, 3 +/- 1 (+/- SEM) vs. 0 +/- 1 pmol/L (P less than 0.05); GRP II, 5 +/- 1 vs. -3 +/- 1 pmol/L; P less than 0.01)]. A further increase in plasma ACTH concentration occurred after cessation of GRP infusion (7 +/- 2 vs. 0 +/- 1 pmol/L; P less than 0.025). GRP caused a similar dose-dependent stimulation of cortisol secretion compared with the effect of saline [delta cortisol before and after treatment: GRP I, -19 +/- 21 vs. -68 +/- 14 nmol/L (P less than 0.05); GRP II, 38 +/- 33 vs. -86 +/- 15 nmol/L (P less than 0.005)]. The serum cortisol concentration increased further after cessation of the GRP infusion (72 +/- 31 vs. -124 +/- 33 nmol/L; P less than 0.0025). GRP dose-dependently stimulated beta-endorphin immunoreactivity compared with the effect of saline [delta beta-endorphin immunoreactivity before and after treatment: GRP I, 6 +/- 1 vs. -3 +/- 1 pmol/L (P less than 0.01); GRP II, 11 +/- 4 vs. -6 +/- 2 pg/mL (P less than 0.025)]. GRP had no effect on PRL or GH secretion. We suggest that GRP participates in the neuroendocrine regulation of the secretion of proopiomelanocortin-derived peptides.

Plasma adrenocorticotropin concentration is elevated in adult rats with neonatal adrenal transplants.

Diurnal rhythms of plasma ACTH and plasma corticosterone concentrations were studied in intact rats at 1, 3, 5, and 7 weeks of age and in bilaterally adrenalectomized adult rats 1, 3, 5, and 7 weeks after transplantation of the neonatal (day 1) adrenal to the anterior chamber of the eye. Whereas there was no difference in adrenal weight or plasma corticosterone concentration between intact and transplanted rats during adrenal development, the plasma ACTH concentration was significantly increased in transplanted rats relative to that in intact rats throughout development. A diurnal rhythm of plasma corticosterone concentration was observed in transplanted rats 5 and 7 weeks after transplantation; however, the onset of the rhythmicity was delayed relative to that of intact rats, who displayed rhythmicity at 3, 5, and 7 weeks of age. Elevated plasma ACTH concentrations in chronically cannulated transplanted rats exhibited diurnal variation in parallel with plasma corticosterone concentrations. Adult rats bearing adult adrenal transplants under the kidney capsule for 5 weeks had plasma ACTH concentrations in the evening that were not different from those in unilaterally adrenalectomized, sham-transplanted rats. In contrast, adult rats bearing neonatal adrenal transplants under the kidney capsule for 5 weeks had increased plasma ACTH concentrations in the evening. Thus, the increased plasma ACTH concentration after adrenal transplantation is dependent on the age of the transplant and not on the site of transplantation. The finding of elevated plasma ACTH concentration associated with normal plasma corticosterone concentration suggests that adrenal responsiveness to ACTH is decreased after transplantation of the neonatal adrenal to the adult rat.

Tooth pulp stimulation potentiates the adrenocorticotropin response to hemorrhage in cats.

Stimulation of the maxillary tooth pulp nerve (TP), a predominantly nociceptive afferent fiber system, was assessed for its effect on peripheral plasma ACTH in chloralose-urethane anesthetized cats. These results were compared to those after a transient 10 ml/kg hemorrhage (H), a submaximal neurogenic stressor for ACTH release, and to H plus TP in combination. TP alone for 3 min had no significant effect on ACTH. However, TP during H greatly potentiated the increase in plasma ACTH concentration compared to that seen after H alone. The TP potentiation of the H-induced rise in ACTH was not accompanied by altered cardiovascular responsiveness nor by differences in plasma norepinephrine or glucose relative to that seen after H alone. The data indicate that nociceptive and baroreceptor afferents share a common neural substrate for selective facilitation of ACTH release, but do not interact to potentiate several other physiological responses, such as sympathetic efferent activity. Furthermore, under the conditions of these experiments, selective nociceptor activation in the anesthetized cat is not an adequate stimulus for the release of ACTH.

Diagnostic and therapeutic implications of ectopic hormone production in small cell carcinoma of the lung.

In 75 unselected and untreated patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, and antidiuretic hormone (ADH) in plasma and urine were related to corresponding clinical symptoms and biochemical findings at the time of diagnosis. The significance of elevated concentrations of these substances in relation to treatment was also investigated. Plasma ACTH concentrations were increased in 22 patients (29%), and 25 patients (33%) were considered to have inappropriate ADH secretion. Only one patient had definite hypokalaemic alkalosis, and one patient pronounced hyponatraemia, with associated clinical syndromes of ectopic ACTH and ADH secretion. Serum calcitonin concentrations were increased in 48 patients (65%). No related clinical symptoms were disclosed, and all these patients had normal serum calcium concentrations. Thirty-three of 66 patients (50%) had raised levels of free cortisol in a 24-hour urine and these levels were significantly related to plasma ACTH concentrations. The median survival was slightly shorter in patients with increased values of the three substances, but this was not related to increased plasma ACTH concentrations and was not statistically significant. Survival rates and results of treatment were independent of the pretreatment levels of the three substances.

Temporal Changes in Plasma Adrenocorticotropin Concentration after Repeated Neurotropic Stress in Male and Female Rats

To test the ability of the pituitary gland to secrete ACTH in response to repeated stress, 90-day-old male and female rats were subjected first to a 3-min psychological stress and then to a second identical stress 5, 10, or 15 min after the onset of the first stress. After decapitation 5, 10, 15, 20, 25, or 35 min after the onset of the second stress, plasma ACTH concentration was determined by bioassay, and plasma corticosterone was measured by a fluorometric method. Although the rate of increase in plasma corticosterone levels after the first stress was about 1.4 μg/100 ml-min in males and 2.1 μg/100 ml-min in females, 5-15 min after the onset of the first stress, no rapid inhibition of the second stress response appeared. Gradual hypersecretion of ACTH occurred in males after exposure to the second stress, and the resultant peak increment in plasma ACTH concentration was 2–3 times greater than the one observed in once-stressed rats. In females, a rapid and significant increase in plasma ACTH concentration occurred, but the ratio was only 0.6:0.9 compared to the control group. These results suggest that the fast feedback inhibition mechanism by endogenous corticosterone is overcome by a more powerful facilitatory effect of the first stress on subsequent ACTH release and that these two antagonistic systems which regulate ACTH release in response to subsequent stress may be sex-related in their onset and magnitude.

Effect of Intraventricular Histamine on Hormone Secretion in Dogs

In pentobarbital-anesthetized dogs, infusion of a low dose of histamine directly into the third ventricle increased plasma ACTH concentration. The increase was unaffected by metiamide, a drug which blocks H2 receptors, but was abolished by mepyramine, a drug which blocks H1 receptors. Mepyramine alone did not produce a decrease in plasma ACTH concentration in stressed dogs. Infusion of the H1 agonist 2-methylhistamine increased plasma ACTH concentration, whereas infusion of the H2 agonist 4-methylhistamine decreased plasma ACTH concentration and blocked the response to surgical stress. Histamine, 2-methylhistamine and 4-methylhistamine had no statistically significant effect on plasma renin activity, blood pressure, or heart rate, and histamine had no effect on plasma prolactin concentration. There were no consistent, specific effects on growth hormone secretion. We conclude that activation of central H1 receptors increases ACTH secretion in dogs, and that activation of central H2 receptors decreases ACTH secretion. Some of the reported effects of cyproheptadine and other drugs on ACTH secretion may be due to their antihistamine activity.

Human plasma immunoreactive β-lipotropin: Correlation with basal and stimulated plasma ACTH concentrations

A sensitive radioimmunoassay for human β-lipotropin (LPH) has been developed utilizing an N-terminal antibody which exhibits no cross-reactivity with β h-MSH and appears to be species specific, with less than 10% crossreactivity with rat, ovine or bovine LPH. 0800-0900 mean plasma LPH concentrations were 47.9±5.7 pg/ml (5 normal subects), 100.5±13.2 pg/ml (Cushing's Disease (CD) n=6), 769.3±390.4 pg/ml (Nelson's Syndrome (NS) n=5). Mean plasma ACTH/plasma LPH ratios were: 1.96±0.13 (normal subjects), 1.69±0.11 (CD) and 1.16±0.07 (NS) Plasma ACTH and LPH rose in parallel in response to insulin-induced hypoglycemia in 4 normal subjects. There was a 375% increase in plasma ACTH concentration, a 474% increase in plasma LPH concentration. Plasma ACTH/LPH ratios in specimens obtained following attainment of peak concentrations were significantly lower than those in either control or peak specimens.

Comparison of plasma corticotropin concentration in intact and adrenalectomized dogs and cats during hemorrhage.

The concentration of ACTH in arterial blood samples from dogs and cats was determined by the adrenal ascorbic acid depletion assay or the plasma corticosterone assay. ACTH was extracted from plasma samples by running acidified plasma through IRC-50 resin columns. The mean recovery of endogenous ACTH in the eluate from these columns was 80%. The mean recovery of exogenous ACTH added to dog blood was 91%. The increase in plasma ACTH concentration induced by hemorrhage in dogs and cats at 2 hr after adrenalectomy was greater than the increase in concentration observed in shamadrenalectomized and intact animals. This marked augmentation of the response to hemorrhage after adrenalectomy suggests that the 80–90% decrease in circulating corticosteroids known to occur in the 2 hr after adrenalectomy is sufficient to increase the rate of release of ACTH during stress. Similar results were obtained when adrenal cortical secretion was reduced by the administration of metyrapone (Su-4885). (Endocrinology 80: 741, 1967)

A sensitive radioimmunoassay for plasma ACTH levels.

We have developed a sensitive and accurate plasma ACTH radioimmunoassay based on that of Yalow and Berson. To increase the sensitivity of the method 5 ml volumes of plasma were extracted with acid acetone and the extracts were purified on a Sephadex column. The mean plasma ACTH concentration in 10 normal subjects at 8 AM was 0.5 mU/100 ml (range 0.3–0.7 mU/100 ml). A diurnal variation in plasma ACTH levels with maxima at 4 and 6 AM was observed in 2 normal subjects. Plasma corticosteroid levels paralleled the plasma ACTH concentrations. Dexamethasone administration suppressed the diurnal variation in both ACTH and corticosteroid levels in one other normal subject. Patients with panhypopituitarism and normal subjects given dexamethasone had 8 AM plasma ACTH concentrations of less than 0.15 mU/100 ml. Untreated patients with adrenal insufficiency or congenital adrenal hyperplasia and patients with Cushing's syndrome usually had increased plasma ACTH concentrations.