Effect of human beta-endorphin on plasma aldosterone concentrations in normal human subjects

beta-Endorphin recently was proposed as a possible physiological stimulus of aldosterone secretion based on studies in animals. Since human beta-endorphin (beta h-endorphin) does not contain the ACTH-(4-10) homology common to other ACTH-related neuropeptides that stimulate aldosterone, its mechanism of stimulation might differ from that of the other peptides. In the present study, we infused beta h-endorphin into six normal subjects under carefully controlled conditions at dosage levels several orders of magnitude higher than endogenous levels. No increase in plasma aldosterone was found in these subjects ingesting a normal sodium intake despite the fact that other biological actions of beta h-endorphin were manifest. By contrast, an equimolar infusion of ACTH-(1-24) caused a significant increase in plasma aldosterone. These studies do not support a significant role for beta h-endorphin in control of aldosterone secretion in man and are consistent with the concept that the ACTH-(4-10) amino acid sequence, common to ACTH, beta-lipotropin, gamma-lipotropin, beta MSH, and alpha MSH, is a major determinant of their aldosterone-stimulating capacity.     

CRF-41 stimulates the release of beta-lipotrophin and beta-endorphin in normal human subjects

A prompt rise in circulating immunoreactive N- and C-terminal lipotrophin (LPH) accompanied the increase in ACTH when 100 micrograms CRF-41 was given to 6 normal male subjects. Chromatography of the basal and peak 15-min values showed that there was an equimolar increase in beta-LPH and beta-endorphin, to cause parallel release of ACTH, beta-endorphin and beta-LPH from the pro-opiocortin precursor.     

Intravenous insulin has no effect on myocardial contractility or heart rate in healthy subjects

Summary To evaluate the acute effects of intravenous insulin on myocardial contractility and heart rate, echocardiography was performed in 12 healthy subjects and continuous heart rate recording in 11 healthy subjects before and during eugly-caemic insulin and glucose infusion. The rate of insulin infusion was 0.5–1.0 mU·kg^–1·min^–1. Serum insulin concentration was increased from 14.1±5.5 (mean±SD) to a plateau level of 91.3±22.8 mU/l. Left ventricular end-diastolic diameter, ejection phase indices and the heart rate remained at basal levels during the intervention. Thus moderate hyperinsulinaemia, induced by euglycaemic insulin and glucose infusion, has no inotropic or chronotropic effects in healthy supine subjects.     

The tetrapeptide AcSDKP, an inhibitor of the cell-cycle status for normal human hematopoietic progenitors, has no effect on leukemic cells.

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) inhibits the entry into DNA synthesis of murine spleen colony-forming units (CFU-S) and protects these cells during chemotherapy. This synthetic peptide also inhibits the growth of normal human marrow progenitors granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) and decreases their percentage in DNA synthesis at nanomolar concentration. In view of its clinical application as a marrow protector, we have investigated its effects on malignant cells. Studies were carried out on HL-60 cells and on fresh leukemic cells from patients with either chronic myeloid leukemia (CML) or acute myeloid leukemia (AML). Results showed that AcSDKP, whatever the doses used, did not modify the proliferation of both HL-60 cells and AML cells even when enhanced by stimulating factors such as interleukin 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, no change in the number and the percentage in S-phase of both HL-60 clonogenic cells and CML progenitors was observed. Our data clearly demonstrate that the tetrapeptide AcSDKP was ineffective on leukemic cells and therefore by acting selectively on normal progenitors represents a potent therapeutical agent for the protection of normal bone marrow progenitors during chemotherapy.     

The effect of diazepam on genioglossal muscle activity in normal human subjects

We examined the effect of diazepam on the respiratory electromyographic (EMG) activity of the genioglossal muscle using a double-blind, placebo-controlled, randomized protocol. Control measurements of minute ventilation, tidal volume, frequency, end-tidal CO2, and peak integrated inspiratory genioglossal EMG activity were made in 10 normal awake male subjects during quiet breathing and CO2 rebreathing. Subjects then received either 10 mg of diazepam orally or a placebo, and all respiratory measurements were repeated after 45 min. Each subject was studied on 2 separate days, receiving each treatment on a different day. The placebo had no effect on any of the measured variables. After diazepam, we observed an increase in end-tidal CO2 rebreathing, diazepam was associated with a reduction in minute ventilation, tidal volume, and frequency. When compared at equal end-tidal CO2 levels, genioglossal EMG activity and tidal volume were significantly reduced after diazepam. However, only older subjects demonstrated a reduction in EMG activity when compared at equal tidal volumes during CO2 rebreathing. We conclude that diazepam selectively decreases genioglossal EMG activity during CO2 rebreathing only in older subjects.     

Short-term hypothyroidism has no effect on serum leptin concentrations

The aim of the study is to determine the effect of short-term hypothyroidism on serum leptin levels. For this purpose 30 patients with past medical history of thyroidectomy for differentiated thyroid carcinoma were included. Serum leptin concentrations were similar when patients were on thyrotrophin-suppressive thyroxine therapy than when were admitted 4 weeks after stopping thyroxine treatment to perform a routine 131I scan in hypothyroid status (17.0 +/- s.e.m. 2.14 vs. 17.6 +/- s.e.m. 2.41 ng/ml; p = n.s.). Moreover, no differences were obtained when the analysis was performed separately in men and in women. We conclude that short-term hypothyroidism does not alter serum leptin concentrations. Furthermore, our results suggest that thyroid hormones do not operate through changes in serum leptin levels to regulate energy expenditure.     

Helicobacter pylori has no effect on plasma ghrelin levels

OBJECTIVE: Helicobacter pylori is the major etiologic agent for chronic active gastritis, and it also plays a crucial role in gastric and duodenal ulcer disease, as well as in gastric carcinoma. H. pylori infection has been shown to decrease plasma somatostatin (SST) and increase plasma gastrin concentrations. Ghrelin is a recently discovered peptide produced mostly in the stomach of rodents and humans and is secreted into the bloodstream. There is no data in the literature about the relationship between H. pylori and ghrelin. DESIGN: Thirty-nine age- and BMI-matched H. pylori infection positive and negative women, from whom biopsy specimens were taken during gastric endoscopy, were included in the study. METHODS: Total ghrelin was measured by enzyme immunoassay (EIA) in Medistek. All samples were measured in duplicate and averaged; results differing by more than 20% were re-assayed. Two biopsy specimens from antrum, corpus and fundus were obtained. RESULTS: Fifteen of the subjects were H. pylori negative and 24 were H. pylori positive. Age, BMI, lipid profile and insulin sensitivity indices of the groups were similar. Plasma ghrelin levels (375.92+/-7.10 vs 370.00+/-4.14 pmol/l; P>0.05) of H. pylori negative and positive groups did not differ significantly. CONCLUSION: H. pylori has no effect on plasma ghrelin concentration.     

Sodium salicylate has no effect on cerebrospinal fluid [H+] in dogs with normal acid-base balance

The experiments described here were designed to investigate the possibility that central stimulation of respiration by salicylates may be due to changes in [H⁺] of cerebral fluids. Two groups (n=6 in each) of anesthetized, paralyzed, and mechanically ventilated dogs were studied for 6 hr. Renal pedicles were ligated to maintain blood salicylate level constant. Group II received 150 mg/kg Na salicylate intravenously at 0 hr after samples had been obtained. Group I (control) received equal volume of half-normal saline. Mean plasma salicylate levels were 18.9, 18.4, and 19.6 mg % at 0.5, 3, and 6 hr after administration of Na salicylate. Respective cisternal cerebrospinal fluid (CSF) levels were 3.2, 4.8, and 5.9 mg %. Salicylate-induced hyperthermia was prevented by peritoneal cold dialysis, and a rise in PaCO₂ was prevented by increasing ventilation. During the 6 hr of relatively normal systemic acid-base balance, cisternal CSF mean PCO₂ values were 45.3, 43.6, and 49.3 mm Hg at 0, 3, and 6 hr in the control group; in group II, respective values were 46.9, 45.7, and 47.7 mm Hg. Cisternal CSF [H⁺] were 44.4, 45.2, and 50.5 nEq/L in group I at 0, 3, and 6 hr. Respective values in group II were 45.0, 47.5, and 50.6 nEq/L. These values were similar and statistically insignificant from those in group I. In both groups cisternal CSF [HCO ₃ ⁻ ] fell about 2 and CSF lactate concentration rose about 1 mEq/L at 6 hr. We conclude that at the dose used in the present study, Na salicylate increases metabolic rate but does not significantly influence cisternal CSF [H⁺] up to 6 hr in dogs with normal systemic acid-base balance.     

Prolonged low-dose dexamethasone, in early gestation, has no long-term deleterious effect on normal ovine fetuses

Low-dose dexamethasone (D) treatment is used in pregnancies where the fetus is suspected to be at risk of congenital/virilizing adrenal hyperplasia. To study if this treatment had any immediate or long-term effects in normal fetuses, pregnant ewes were treated with D (20 microg/kg maternal body weight x d) or saline (S), from d 25-45 of gestation. Tissue was collected from fetuses killed at 45 d (S = 6; D = 8), 130 d (S = 8; D = 8), or lambs at 2 months of age (S = 6; D = 6) and mRNA levels measured using real-time PCR. D treatment reduced adrenal wt at 45 d (S, 12.2 +/- 0.7 mg; D, 6.3 +/- 0.4 mg) and significantly decreased adrenal mRNA for P(450scc). At 130 d, fetuses from the D treatment were growth retarded (S, 3.2 +/- 0.1 kg; D, 2.5 +/- 0.1 g), but the adrenals were appropriate for the body weight. mRNA levels of angiotensinogen, the AT(1) receptor and mineralocorticoid receptor (MR) and GR were similar in kidney and brain (hypothalamus, hippocampus, medulla oblongata) except for hippocampal expression of MR and GR, which was significantly decreased by D treatment. By 2 months, BW and hippocampal MR and GR mRNA levels were similar, and lambs were normotensive (S, 83 +/- 3 mm Hg; D, 78 +/- 3 mm Hg). Thus, there were no persistent, long-term effects of prolonged low-dose D treatment in normal ovine fetuses.     

Sodium salicylate has no effect on cerebrospinal fluid [H+] in dogs with normal acid-base balance

The experiments described here were designed to investigate the possibility that central stimulation of respiration by salicylates may be due to changes in [H+] of cerebral fluids. Two groups (n = 6 in each) of anesthetized, paralyzed, and mechanically ventilated dogs were studied for 6 hr. Renal pedicles were ligated to maintain blood salicylate level constant. Group II received 150 mg/kg Na salicylate intravenously at 0 hr after samples had been obtained. Group I (control) received equal volume of half-normal saline. Mean plasma salicylate levels were 18.9, 18.4, and 19.6 mg % at 0.5, 3, and 6 hr after administration of Na salicylate. Respective cisternal cerebrospinal fluid (CSF) levels were 3.2, 4.8, and 5.9 mg %. Salicylate-induced hyperthermia was prevented by peritoneal cold dialysis, and a rise in PaCO2 was prevented by increasing ventilation. During the 6 hr of relatively normal systemic acid-base balance, cisternal CSF mean PCO2 values were 45.3, 43.6, and 49.3 mm Hg at 0, 3, and 6 hr in the control group; in group II, respective values were 46.9, 45.7, and 47.7 mm Hg. Cisternal CSF [H+] were 44.4, 45.2, and 50.5 nEq/L in group I at 0, 3, and 6 hr. Respective values in group II were 45.0, 47.5, and 50.6 nEq/L. These values were similar and statistically insignificant from those in group I. In both groups cisternal CSF [HCO3-] fell about 2 and CSF lactate concentration rose about 1 mEq/L at 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Theophylline blunts the GH-response to growth hormone releasing hormone in normal subjects

Theophylline enhances GH-secretion in vitro, whereas in vivo a slight decrease of basal GH-levels has been observed. In the present study the effect of theophylline on the GH-responsiveness to acute and continuous administration of growth hormone releasing hormone (GHRH) was investigated. The following protocol was performed. GHRH study. Fifty micrograms GHRH was given as an iv bolus followed by constant GHRH-infusion (100 micrograms/h) over 2 h after which another GHRH bolus of 50 micrograms was given. GHRH plus theophylline study. GHRH was administered as in the first study and theophylline was infused at a constant rate of 3.56 mg/min over 3 h, starting one h before the GHRH bolus. Theophylline study. Only saline and theophylline were infused. GHRH alone led to a GH-rise within 30 min with a maximum of 22.8 +/- 7.2 ng/ml (mean +/- SE) after which GH-levels decreased despite continuous GHRH-infusion to a nadir of 12.1 +/- 4.4 ng/ml at 105 min. The second GHRH bolus led to a minimal GH-increase (13.3 +/- 6.4 ng/ml at 135 min). Theophylline administration resulted in blunting of the GH-response to GHRH in all volunteers, with GH levels fluctuating between 4-6 ng/ml throughout GHRH-administration. Theophylline alone did not affect GH-levels in three subjects studied, whereas in the other one a GH secretory episode 90 min after administration of the drug was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of hypermagnesaemia on serum immunoreactive calcitonin levels in normal human subjects

The effect of hypermagnesaemia on serum levels of immunoreactive calcitonin was studied in normal human subjects. After iv administration of magnesium sulphate over 120 min, the mean (+/- SEM) serum magnesium concentration rose from the baseline level of 0.9 +/- 0.1 to 2.6 +/- 0.3 mmol/l (P less than 0.01), and thereafter remained higher than the baseline level. The magnesium infusion caused a significant increase in serum immunoreactive calcitonin levels (P less than 0.01). The rise in serum magnesium concentration was accompanied by a significant decrease in the concentrations of corrected serum calcium and whole blood ionized calcium (P less than 0.01, P less than 0.01 respectively). Our results suggest that hypermagnesaemia causes an increase in serum immunoreactive calcitonin levels in normal human subjects despite a decrease in the concentrations of corrected serum calcium and whole blood ionized calcium.     

Famotidine has no significant effect on gonadal function in man

The effect of a single bedtime dose of famotidine 40 mg on gonadal function was studied in 8 male duodenal ulcer patients. The drug was orally administered for 4 weeks. Our results show that this new H2 blocker influences basal and stimulated serum levels of neither testosterone nor gonadotrophins (LH, FSH). Besides, no significant variations were observed before and after famotidine treatment in seminal fluid characteristics evaluated in 5 out of 8 cases. It can be concluded that famotidine appears to leave gonadal function unaffected in man.     

Growth hormone has no direct effect on human adrenal steroid and insulin-like growth factor-binding protein secretion

Although it is known that growth hormone (GH) exerts its growth-promoting effects mainly via Insulin-like growth factor-I (IGF-I), an increasing number of direct effects of GH has been described in many tissues. In vivo, mice transgenic for human growth hormone (hGH) show significantly elevated levels of corticosterone, enlarged adrenal glands, and altered levels of insulin-like growth factor binding proteins (IGF-BPs). Recently, we have shown that IGF's induce the secretion of cortisol and IGF-BP's in adult human adrenocortical cells. However, since human adrenal glands express the intact GH-receptor, the objective of this study was to investigate whether GH exerts a direct effect on the steroidogenesis and IGF-BP synthesis in adult human adrenocortical cells. Primary cell cultures in monolayer were incubated under serum-free conditions with human growth hormone and/or ACTH for up to 72 hours. Cortisol was measured by specific RIA and the secretion of insulin-like growth factor binding proteins was analyzed by Western ligand blotting. hGH alone was unable to stimulate basal or ACTH-induced cortisol secretion. Additionally, neither hGH alone or in combination with ACTH did significantly alter the secretion of IGF-BP's. Therefore we conclude that hGH is unable to directly stimulate cortisol secretion and IGF-BP secretion in cultured human adrenocortical cells.     

Porcine pancreastatin has no effect on endocrine secretion from the pig pancreas

Summary We investigated the effects of porcine pancreastatin on the endocrine and unstimulated exocrine secretion of isolated, perfused porcine pancreas. Pancreastatin in a concentration of 10^–8mol/l had no effect on basal secretion of insulin, glucagon and somatostatin at a perfusate glucose concentration of 5 mmol/l (n=4) and neither at 10^–8 nor 10^–7 mol/l influenced the hormone responses to acute elevations of perfusate glucose concentration from 3.5 to 11 mmol/l (n=7). This elevation strongly stimulated insulin secretion and inhibited glucagon secretion. Exocrine secretion was not affected by pancreastatin. The results suggest that pancreastatin does not directly influence pancreatic secretion.