Effect Of ACTH Administration Research Articles

Effects of ACTH administration on zonation of the guinea pig adrenal cortex

Experiments were done to determine the actions of ACTH on the morphologic and functional characteristics of the zona fasciculata (ZF) and zona reticularis (ZR) in the guinea pig adrenal cortex. In control guinea pigs, a number of morphologic differences distinguished the ZF from the ZR, including the presence of far more lipid in the ZF than in the ZR. Treatment with ACTH decreased the lipid droplet content of the ZF cells, equalizing the amount of lipid in the two zones. Other morphologic differences between the ZF and ZR were also diminished by ACTH treatment. Immunohistochemical analyses indicated that CYP17 protein was found in both the ZF and ZR in control animals, but with greater immunostaining intensity in the ZF. The enzyme protein distribution corresponded with higher 17 α-hydroxylase activity in the ZF than in the ZR. After ACTH treatment, the intensity of staining and enzyme activities in the two zones were similar, attributable largely to increases in the ZR. In situ hybridization and immunohistochemistry showed that in control animals CYPD216 was highly expressed in the ZR but not in the ZF. ACTH treatment dramatically reduced the intensity of CYP2D16 mRNA and protein staining in the ZR. Bufuralol 1′-hydroxylase activity, a marker for CYP2D subfamily members, was also decreased significantly in the ZR by ACTH treatment. The data indicate that administration of ACTH to guinea pigs has opposite effects on the expression of CYP17 and CYP2D16 in the ZR, and diminishes or eliminates some of the structural and functional differences between the ZF and ZR. The results suggest a role for ACTH in establishing and maintaining adrenocortical zonation.

A short negative feedback mechanism regulating corticotropin-releasing hormone release.

The effect of ACTH administration on plasma CRH levels was studied. In five patients with Addison's disease and three patients with hypopituitarism, bolus iv injection of 0.25 and 0.5 mg ACTH-(1-24) reduced plasma CRH levels (that had become elevated 48 h after discontinuation of corticosteroid replacement) to near-normal levels at 30-60 min in a dose-dependent manner. Plasma immunoreactive beta-endorphin levels were similarly decreased in patients with Addison's disease. ACTH-(1-24) (0.25 and 0.5 mg) injection failed to inhibit plasma CRH levels in five normal subjects. Basal CRH release from the rat hypothalamic median eminence in vitro was inhibited by 0.22 and 2.2 nM ACTH-(1-24) and ACTH-(1-39) in a dose-dependent manner. These results suggest that in the absence of negative feedback control of ACTH secretion by glucocorticoids, ACTH can regulate its secretion by inhibition of hypothalamic CRH release.

Loss of sensitivity to morphine induced by prolonged ACTH treatment

The effect of long term ACTH treatment on some actions of morphine were studied. The effect of ACTH administration was compared to that induced by acute dexamethasone injection. ACTH caused a delayed inhibition of the morphine induced increase in growth hormone secretion demonstrable 24 hr after the last hormone injection. The morphine induced increase of striatal DOPAC (3,4-dihydroxyphenylacetic acid) content was also inhibited by ACTH treatment, however, neither the analgesia, nor the hypermotility caused by morphine were affected. Dexamethasone did not alter significantly the responsiveness to morphine. It is concluded that the prolonged exposure to ACTH presumably causes a corticosterone-mediated loss of responsiveness of functionally restricted opiate sensitive mechanisms in the central nervous system.

Effect of ACTH administration on urinary kallikrein excretion in man.

The effect of ACTH administration on urinary kallikrein excretion and its relationship to changes in plasma and urine electrolytes, renin concentration and steroids was examined in normotensive and mildly hypertensive subjects. ACTH administration produced hypokalaemia, initial urinary sodium retention, a fall in active plasma renin concentration, a transient rise in plasma aldosterone concentration and sustained rises in plasma deoxycorticosterone concentration and urinary kallikrein activity. Changes in patients with mild hypertension were similar in pattern to normotensives, but urinary kallikrein concentrations were lower. The effects of ACTH on urinary kallikrein excretion appeared to be independent of aldosterone and correlated most closely with deoxycorticosterone concentrations.

Effect of adrenocortical steroids and their structural analogues on blood pressure in sheep.

1. A model of adrenocortical steroid-induced hypertension based on the effects of ACTH administration has been developed in sheep. The present studies examine the effects of a number of different steroid hormones on blood pressure to investigate their structure-activity relationships. 2. Infusion of the major ovine adrenal steroid hormones (combined steroid infusion of cortisol, corticosterone, 11-deoxycortisol, aldosterone, deoxycorticosterone) reproduced the metabolic but not the blood pressure effects of ACTH. 3. Addition of 17 alpha, 20 alpha-dihydroxyprogesterone and 17 alpha-hydroxyprogesterone, at rates appropriate for conditions of ACTH stimulation, to the combined steroid infusion reproduced both the blood pressure and metabolic effects of ACTH. 4. 17 alpha-20 beta-Dihydroxyprogesterone, 20 beta-dihydroxy-11-deoxycortisol and 20 beta-hydroxycortisol all had additional hypertensive activity when given with combined steroid infusion, but 16 alpha-hydroxyprogesterone, 11 beta, 17 alpha-dihydroxyprogesterone, 20 alpha-hydroxyprogesterone and 20 beta-hydroxyprogesterone did not. 5. These studies support the concept of a new class of steroid hormone action in blood pressure regulation.

The development of fetal adrenal function.

The response profiles of fetal sheep adrenals to tropic stimulation have been examined ih vivo and in vitro. Isolated adrenal cells from sheep fetuses in early pregnancy (Day 50) reduced cortisol in response to ACTH, dibutyryl cyclic AMP and GTP. The response was minimal on Day 100, but reappeared near term. 17 alpha-Hydroxyprogesterone was converted to cortisol by adrenals of all ages, but pregnenolone and progesterone were converted to cortisol only in early and late, but not mid-pregnancy. These studies suggested that the mid-gestation loss of fetal adrenal responsiveness was associated with post-receptor/adenylate cyclase events and involved loss of 17 alpha-hydroxylase activity. Fetal adrenal function was activated by exogenous ACTH in vivo, and was reflected in an increase in the ratio of cortisol to corticosterone in fetal plasma and in augmented cortisol output in vitro from dispersed fetal adrenal cells. The results were consistent with an effect of ACTH administration on 17 alpha-hydroxylation. Fetal pituitary cells, prostaglandin E2, alpha-MSH and term placental extract are other potential (sources of) corticotropins, although further studies are required to delineate the nature and origin of the active substances, and/or their primary sites of action.

Urinary Excretion of 3β-hydroxy-Δ<SUP>5</SUP>-steroids in the Newborn Infant and the effect of ACTH Administration

The urinary 3β-hydroxy-Δ5-steroids excreted during the period of the first week by newborn infants were analyzed by means of gas chromatography and gas chromatography-mass spectrometry to study the changes in the amount of these steroids. The changes in the amount of each steroid after the administration of ACTH were also studied. The results are summarized as follows : 1) Seven kinds of 3β-hydroxy-Δ5-steroids were identified in the urine of the newborn infants. 17a, 21-dihydroxypregnenolone was newly identified.2) The daily changes in the amount of each of these steroids differed. Generally, the amount of the C-19 steroids increased day by day and that of the C-21 steroids decreased during the period of our observation.3) After the administration of ACTH, the amount of these urinary steroids excreted increased at nearly the same rate.

The Effect of ACTH Administration on Serum Estrogens, LH, and FSH in the Aged

The effect of administration of long acting ACTH on serum levels of estrogens, LH and FSH was studied in aged subjects. Nine women and 5 men between 66 and 90 years of age were examined. One milligram of long-acting synthetic ACTH was given in every 12 h for 2 days. Significant increases in serum estrone and estradiol levels were induced in parallel with serum cortisol at 24 hours and no further change was observed at 48 hours. The estrone/estradiol ratio increased from a control value of 3.0 to 4.0 at 24 hours and to 4.7 at 48 hours (P less than 0.02) compared to control values.

The Effect of ACTH Administration on the Phagocytic and Bactericidal Activities of Human Polymorphonuclear Leukocytes

Metabolic and bactericial activities of leukocytes obtained from 5 normal volunteers receiving 1 mg of synthetic B1-24 ACTH intra-muscularly daily for 7 days, were studied. Bactericidal activity and phagocytosis induced hexosemonophosphate shunt activity of leukocytes were found to be depressed following ACTH administration. However, glycolytic activity, which provides the necessary energy for particle uptake by leukocytes, was not altered. These findings indicate that a moderately prolonged exposure to elevated levels of plasma cortisol does not affect the phagocytic activity of leukocytes (as indicated by glycolytic activity) but significantly impairs their ability to destroy the ingested bacteria. It is suggested that the impaired bactericidal activity of leukocytes reported in children suffering from protein-calorie malnutrition may partly be due to elevated plasma cortisol levels seen in them.

48. Effect of ACTH administration into the fetus, on onset of labour and on maternal plasma steroid levels

48. Effect of ACTH administration into the fetus, on onset of labour and on maternal plasma steroid levels

The effect of acth administration on plasma testosterone, dihydrotestosterone and serum lh concentrations in normal men

Plasma cortisol (F), testosterone (T), dihydrotestosterone (DHT) and serum luteinizing hormone (LH) concentrations were measured in 8 normal young men at 8 AM on two control days. Exogenous adrenocorticotrophin (ACTH) 20 U.S.P. units per m 2 of body surface area every 12 or 6 hours was administered intramuscularly for 4 days. Twenty-four hours after starting ACTH administration, the plasma T and DHT concentrations were significantly lower than those of the control days on a paired t test. No significant change in serum LH concentration could be demonstrated. Similar results were observed after 48, 72 and 96 hours of ACTH stimulation.

Effect of ACTH on the phosphorylation of proteins in subcellular fractions of rat adrenal glands.

To elucidate the role of cAMP-dependent protein kinase in steroidogenic action of ACTH, effect of ACTH administration on the rate of protein phosphorylation in the adrenal subcellular fractions were examined by injecting 32P-orthophosphate to rats 30 min before the death of animals. Bulk of the radioactivity was observed in the alkali-labile phosphorous from the nuclear fraction. Administration of ACTH caused a significant elevation in the radioactivity of the microsomal protein when compared on weight basis protein but the radioactivity in the other three fractions was not changed by the same treatment of animals. These results appeard to provide another evidence for that the site ACTH action mediated by cAMP is localized in microsomal fraction of rat adrenals.

The effect of ACTH administration on aldosterone production in non salt-losing congenital adrenal hyperplasia.

ABSTRACT The effects of adrenocorticotropin stimulation (ACTH-gel, im for 3 days in a dose of either 20 IU/m2/every 12 hr or 20 IU/m2/ every 6 hr) on aldosterone secretion rate and plasma levels of cortisol and aldosterone were studied in seven patients with non salt-losing congenital adrenal hyperplasia (CAH) while on replacement steroid therapy and in ten normal individuals. All subjects were placed on a constant Na and K intake. When ACTH was given every 6 hr, there was a sustained increase of plasma cortisol in control subjects (mean ± sd on 3rd stimulation day: 48 ± 4 μg/100 ml), whereas the values of the patients were brought up to levels expected of normal, unstimulated individuals (mean ± sd on 3rd stimulation day: 13 ± 3 μg/100 ml). Elevation of plasma aldosterone occurred in both control subjects and patients, but the values of the patients remained significantly higher than those of the controls. By the third day of ACTH stimulation the mean (± sd) values of the patients were still elevated (47...

The effect of ACTH administration upon activity-related self-starvation

All Ss lived on a 23-h food-deprivation schedule. Two experimental groups lived in activity wheels while two control groups lived in laboratory cages. One experimental and one control group received subcutaneous injections of ACTH, while the other two groups received injections of physiological saline. The ACTH injection had no effect on the self-starvation phenomenon, and the results are in opposition to the hypothesis of adrenocortical involvement in the phenomenon.

Changes in the activity of rat adrenal ribonuclease and ribonuclease inhibitor after administration of corticotrophin

In an attempt to throw some light on the effect of ACTH administration on the amount of RNA in the rat adrenal gland, studies have been carried out on the levels of ribonuclease (polyribonucleotide: 2-oligonucleotidotransferase (cyclizing), EC 2.7.7.16), both “free” and “latent”, and ribonuclease inhibitor in the gland. The amount of “free” ribonuclease was found to be very small. “Latent” ribonuclease, whose activity was unmasked by treatment with p-chloromercuribenzoate, was much higher in amount. The p-chloromercuribenzoate probably breaks the bond between the ribonuclease and a naturally-occurring inhibitor which appears to be similar to the inhibitor detected in rat liver. After 18 h of ACTH treatment, the activity of the “latent” ribonuclease appeared to be lowered. Administration of ACTH increased the activity of the ribonuclease inhibitor, the increase being especially marked after 18 h. It is thus concluded that at least part of the mechanism whereby ACTH increases the amount of RNA in the adrenal can be attributed to elevated levels of this inhibitor.

FURTHER STUDIES ON THE STIMULATION OF ADRENAL PROTEIN SYNTHESIS BY ACTH: AN EFFECT ON MICROSOMES AND RIBOSOMES.

The effects of ACTH administration on in vitro incorporation of 14C-glycine into protein in cell-free systems of the rat adrenal have been studied. When incubated with 105,000 ×g supernatant (from control or ACTH-stimulated adrenals) in an amino acid incorporating system, the microsomes from ACTH-stimulated adrenals were more active for 14C-glycine incorporation than equivalent amounts of control microsomes. This effect was also demonstrable in ribosomes isolated by desoxycholate extraction of microsomes, indicating that the effect of ACTH on adrenal microsomes is due to changes in the ribosomal fraction. Ribosomes from ACTH-stimulated adrenals were more active than control ribosomes when compared either on a gramequivalent basis or in terms of ribosomal- RNA. These results indicate that ACTH administration enhances the capacity of adrenal microsomes for incorporation of 14C-glycine into protein by induction of an increased amount and activity of ribosomal-RNA. (Endocrinology 74: 579, 1964)

Influence of the Adrenal Cortex on Renal Hemodynamics in the Dog

The effect of ACTH administration on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), effective renal blood flow (ERBF) and on filtration fraction (FF) was studied in unanesthetized female dogs before and after the production of atrophic changes in the zonae reticularis and fasciculata of the adrenal cortex. The atrophic changes were produced by Rhothane (DDD) which has been shown to produce changes in the two inner zones of the adrenal cortex. The administration of ACTH to normal dogs caused a considerable increase in GFR, ERPF, ERBF, and a significant decrease in FF. The administration of DDD resulted in varying degrees of necrosis and atrophy of the zonae fasciculata and reticularis of the adrenal cortex with minimal histological evidence of glomerulosa damage. There was a concomitant decrease below control values for the renal function studied in three of five dogs. The subsequent administration of ACTH restored the renal functions to the control level in all five dogs, with the exception of FF. The simultaneous administration of ACTH and Rhothane resulted in a progressive decrease to or below control values from elevated levels in three of five dogs studied. In one dog there was no appreciable elevation of renal function with ACTH under these conditions. In the other dog ACTH administration was continued uninterrupted, and the addition of Rhothane abolished the renal stimulating effect of ACTH within five days. It is concluded that the two inner zones of the adrenal gland influence renal hemodynamics, as manifested by the stimulating effect of ACTH and the depressing effect of Rhothane.

The Effect of ACTH Administration on the Urinary Excretion of Androgens and Other Steroids by Old Men in Comparison with Young Men: Preliminary Report

The Effect of ACTH Administration on the Urinary Excretion of Androgens and Other Steroids by Old Men in Comparison with Young Men: Preliminary Report

Nonconjugated adrenocortical steroids in human plasma: comparison of the Nelson of Samuels method with paper chromatographic techniques.

In Recent years the method of Nelson and Samuels (1) for the determination of free 17-hydroxycorticosteroids (17-OH-CS) in human plasma has been used extensively. Studies of normal levels of 17-OH-CS and the effect of ACTH administration on these levels have been made (2, 3, 4). During medical or surgical stress an increase in the concentration of plasma 17-OH-CS was observed (5) and a marked rise in the levels prior to death was reported by Sandberg et al. (6). Studies of 17-OH-CS levels in schizophrenic patients under various conditions have also been carried out (7, 8). It should be noted that the Nelson and Samuels method does not measure the corticoid conjugates which have been detected recently in human blood (9).

Effect of ACTH administration on certain enzyme systems in rat liver.

Summary1.0 mg ACTH was injected into rats for 8-10 days. Liver slices from these animals showed a decreased methylation of nicotinamide and an increased methylation of guanidoacetic acid. The methylation of homocysteine was unaffected. Tyrosine formation from phenylalanine was inhibited as was uric acid formation from xanthine. Urea production was normal. Endogenous ketone body production and the oxidation of octanoate was increased.