Short term cardiovascular effects of aldosterone in healthy male volunteers.

Clinical evidence of rapid, nongenomic aldosterone effects in the cardiovascular system has been provided by clinical studies; an increase in systemic vascular resistance (SVR) was shown by invasive techniques within 3 min after injection of aldosterone. Here, we study the dose dependency and the later course of the rapid aldosterone effects by noninvasive techniques. In 12 healthy male volunteers, SVR and heart rate variability were determined by impedance cardiography and digital electrocardiography, respectively, for 8 h after the injection of 0.05 or 0.5 mg aldosterone in a double blind, placebo-controlled, 3-fold cross-over study. No significant differences were observed for baseline values among the three treatments. The area under the curve of SVR during the first 45 min after injection was significantly different between the periods with the highest areas under the curve seen after the injection of 0.5 mg aldosterone (mean +/- SD, 40.4 +/- 12.8 vs. 36.8 +/- 10.3 for 0.05 mg aldosterone and 36.8 +/- 10.4 for placebo; P = 0.05). Individual comparisons showed significant differences at 6 and 30 min between placebo and the 0.5 mg aldosterone period (P < 0.05), with values for the 0.05 mg aldosterone period similar to those for the placebo period. From 330-390 min, opposite changes occurred; SVR was depressed during the 0.05 mg (P < 0.05) and 0.5 mg aldosterone periods compared with that during the placebo period. These delayed effects may reflect an increased vagal tone in the aldosterone groups, as demonstrated by higher values of the time domain parameter of heart rate variability pNN50. This study provides further evidence for clinically detectable rapid cardiovascular aldosterone effects in vivo obtained by noninvasive techniques. The data are consistent with the view of aldosterone as a rapid modulator of cardiovascular responses acting through nongenomic mechanisms.     

Mirtazapine decreases stimulatory effects of reboxetine on cortisol, adrenocorticotropin and prolactin secretion in healthy male subjects

Reboxetine is a selective noradrenaline reuptake inhibitor, whereas mirtazapine acts as an antagonist at noradrenergic alpha(2), serotonin (5-HT(2)), 5-HT(3) and histamine H(1) receptors. In a former study we could demonstrate an inhibitory impact of mirtazapine on cortisol secretion. In the present investigation, the influence of combined administration of 15 mg mirtazapine and 4 mg reboxetine on the cortisol (COR), adrenocorticotropin (ACTH), growth hormone (GH), and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to reboxetine alone (4 mg). In a randomized order, the subjects received reboxetine (4 mg) alone or the combination of reboxetine (4 mg) and mirtazapine (15 mg) at 8:00 a.m. on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to the administration of single reboxetine or the combination (reboxetine and mirtazapine), at time of administration, and during the time of 5 h thereafter in periods of 30 min. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. For statistical evaluation, the Wilcoxon signed-ranks test was performed. There was a pronounced stimulation of COR, ACTH, GH, and PRL concentrations after single administration of reboxetine. When reboxetine was given in combination with mirtazapine, a significant reduction of the COR, ACTH, and PRL stimulation was observed whereas GH secretion patterns remained unchanged, compared to single administration of reboxetine. Apparently, the stimulatory effects of reboxetine on pituitary hormone secretion via noradrenergic mechanisms are counteracted in part by the alpha(2)-blocking properties of mirtazapine and its inhibitory influence on cortisol secretion.     

The effects of the aromatase inhibitor fadrozole hydrochloride on fetuses and uteri in late pregnant rats

It is well known that progesterone and estrogen are essential hormones for maintaining pregnancy in most mammals. Some specific roles of progesterone for the maintenance of pregnancy have been clarified, but the role of estrogen is not well known. This study examines the effects of the aromatase inhibitor, fadrozole hydrochloride (Fad), on fetuses, uterine physical properties and the mRNA expression of the uterine enzymes that are related to collagen metabolism during late pregnancy in rats. Continuous s.c. infusion with 300 micro g/day Fad from day 14 of pregnancy (day 1=the day of sperm detection) reduced the concentration of plasma estradiol-17beta (E(2)), and did not change that of plasma progesterone, compared with controls. The treatment increased the intrauterine pressure and reduced the size and compliance of the uterine tissue framework. It also caused injuries (hematomata on the extremities) in about one-quarter of fetuses by day 20. The collagen content of the uterine ampullae was not changed by the treatment. Uterine mRNA expressions of matrix metalloproteinase-1 (MMP-1), which degrades collagens, and of lysyl oxidase (LO), which is necessary for the formation of intra- and inter-molecular cross-links of collagen, were examined by quantitative RT-PCR. The treatment with Fad had no effect on the expression of MMP-1 mRNA and increased that of LO mRNA. Daily s.c. injection with 0.2 micro g E(2) restored the changes in uterine physical properties and the mRNA expression of LO caused by the Fad treatment, and prevented fetal injury, indicating that the influences of Fad treatment are due to estrogen deficiency but not to toxicological effects of Fad. These results imply that estrogen deficiency during late pregnancy in rats obstructs development of the uterine tissue framework so as to cause fetal injury. It is possible that an increase in the uterine expression of LO gene may be involved in this obstruction.     

Ketanserin without effects on basal anterior pituitary hormone secretion in healthy subjects

The effect of ketanserin, a selective serotonin-2 (5-HT2) receptor blocking agent, on the secretion of anterior pituitary hormones was studied in 4 healthy volunteers. Ketanserin (10 mg) was administered as a slow iv injection and its effect was compared with that of saline. Ketanserin influenced neither the basal plasma levels of HGH, ACTH, TSH, LH or prolactin, nor the plasma levels of T4, T3, cortisol or glucose. Even if a single dose of ketanserin had no hormonal effects, this must also be studied after long term use.     

Clinical trial: inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects

Background and Aim: Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. Methods: In a double‐blind, three‐way cross‐over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24‐h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics. Results: Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose‐dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (P < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups. Conclusions: Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid‐related disease.     

Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects.

There is evidence that melatonin may play a role in modulating pituitary secretion, although the mechanisms are unclear. We examined the effects of a single dose of oral melatonin (5mg) on exercise-induced GH secretion. In a randomised, double-blind, placebo-controlled study, seven healthy male subjects undertook an initial period of graded bicycle ergometric exercise to determine maximum workload and oxygen uptake (VO(2max)). Subjects were subsequently studied on two further occasions, receiving either melatonin or placebo in random order at the onset of each study (-60min). At 0 min a period of bicycle exercise was performed for 8 min at a workload corresponding to 70% of that achieved at VO(2max). Serum GH and IGF-binding protein-1 (IGFBP-1) concentration was measured at 15-min intervals from the onset of the study until 120 min post-exercise. Blood was also sampled for the measurement of plasma glucose, insulin, non-esterified fatty acids, IGFBP-3, melatonin and vasopressin concentration. There was an exercise-induced increase in GH concentration following melatonin which was greater compared with placebo as assessed by both area under the curve (P<0.01) and peak increase in GH levels (P<0.01). The peak increase in IGFBP-1 levels post-exercise was also significantly greater following melatonin compared with placebo (P<0. 01) but did not quite reach levels of significance as measured by area under the curve (P=0.07). Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level.     

Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects

Summary Our study investigates short- and long-term effects of infusion of non-esterified fatty acids (NEFA) on insulin secretion in healthy subjects. Twelve healthy individuals underwent a 24-h Intralipid (10% triglyceride emulsion) infusion at a rate of 0.4 ml/min with a simultaneous infusion of heparin (a bolus of 200 U followed by 0.2 U/min per kg body weight). After an overnight fast (baseline), at 6 and at 24 h of Intralipid infusion and 24 h after Intralipid discontinuation (recovery test), all subjects underwent an intravenous glucose tolerance test (iv-GTT) (25 g of glucose/min). Intralipid infusion caused a threefold rise in plasma NEFA concentrations with no difference between the 6- and the 24-h concentrations. Compared to baseline acute insulin response (AIR) (AIR=63±8 mU/l), short-term (6-h) Intralipid infusion was associated with a significant increase in AIR (86±12 mU/l p<0.01); in contrast, long-term (24-h) Intralipid delivery was associated with inhibition of AIR (31±5 mU/l) compared to baseline (p<0.001) and to the 6-h (p<0.03) triglyceride emulsion infusion. Intralipid infusion was associated with a progressive and significant decline in respiratory quotient (RQ). A positive correlation between changes in fasting plasma NEFA concentrations and AIR at the 6-h infusion (r=0.89 p<0.001) was found. In contrast, at the end of the Intralipid infusion period, changes in plasma NEFA concentrations and AIR were negatively correlated (r=–0.87 p<0.001). The recovery test showed that fasting plasma NEFA concentrations, RQ and AIR had returned to baseline values. In the control study (n=8) 0.9% NaCl infusion did not mimick the effect of Intralipid. In conclusion, our study demonstrates that short- and long-term exposures of beta cells to high plasma NEFA concentrations have opposite effects on glucose-induced insulin secretion.Abbreviations NEFA Non-esterified fatty acids - ivGTT intravenous glucose tolerance test - AIR acute insulin response - NIDDM non-insulin-dependent diabetes mellitus     

The progressive effects of ageing on chemosensitivity in healthy subjects

The aim of this study was to compare the central inspiratory drive (P(0.1)) response to hypoxia and hypercapnia between different age groups of elderly, nonsmoker, healthy subjects and young healthy controls. A random sample, proportionally stratified by age (65-69, 70-74, 75-79 and 80-84 yrs) from a sample of nonsmoker elderly subjects representative of a general population and 47 healthy subjects aged 20-40 were selected. Arterial blood gas, lung volumes, diffusing capacity, maximal respiratory pressure and oxygen uptake measurements were performed. Breathing pattern and mouth occlusion pressure, as well as P(0.1) responses to hyperoxic progressive hypercapnia and isocapnic progressive hypoxia were evaluated. The elderly subjects had lower P0.1 responses to hypoxia (0.017+/-0.006 vs. 0.031+/-0.008 kPa/%, P<0.001) and hypercapnia (0.042+/-0.018 vs. 0.051+/-0.030 kPa/mmHg, P=0.047) than the young healthy controls. Hypoxic sensitivity gradually decreased as age increased to 70-74 and remained unchanged from 75 years of age onward. CO(2) threshold was lower in the elderly groups than in young healthy controls. Lung volumes, inspiratory muscle strength and baseline metabolic rate were the principal determinants of hypoxic sensitivity. In summary, during old age, a progressive decline in hypoxic sensitivity and a decrease in the CO(2) threshold are experienced. These alterations remain stable from the age of 75 onward.     

Effect of cimetidine on histamine- and pentagastrin-stimulated gastric secretion in healthy subjects.

Cimetidine-induced inhibition of gastric acid and pepsin secretion in response to histamine and pentagastrin simulation was studied in four healthy young subjects. Different doses of histamine and pentagastrin were administered alone and in combination with cimetidine on separate days; the order of administration was randomized. As the dose of histamine increased, the inhibitory effect of 0.6mg.kg-1h-1 of cimetidine on acid output decreased. With supramaximal histamine stimulation the inhibition was completely overcome. These results are consistent with competitive inhibition of histamine-stimulated acid output by cimetidine in man. After pentagastrin stimulation inhibition of acid output by cimetidine could not be overcome by increasing the dose of the stimulant, suggesting a noncompetitive inhibition of pentagastrin-evoked acid output. It is concluded that the kinetics of cimetidine-induced inhibition of histamine- and pentastrin-stimulated gastric acid output are different. At approximately half maximal stimulation of acid secretion, cimetidine was a more potent inhibitor of histamine than of pentagastrin. Pepsin output in response to both histamine and pentagastrin stimulation was also inhibited by cimetidine.     

Effect of carbacholine and urecholine on pentagastrin-stimulated gastric secretion in healthy subjects.

Dose-response studies of pentagastrin-stimulated gastric secretion were performed in 6 healthy volunteers. On different days pentagastrin was given in doses of 0.15, 1.5, and 15 mug/kg/hr either alone or in combination with carbacholine, 2 mug/kg/hr, or urecholine, 60 mug/kg/hr. Carbacholine and urecholine increased acid and pepsin secretion evoked by the lowest dose of pentagastrin while there was no augmentation at the highest dose. The dose of pentagastrin required to elicit half maximal acid output (Km) tended to decrease by simultaneous infusion of carbacholine or urecholine, suggesting that the cholinomimetics increased the sensitivity of the parietal cells to pentagastrin stimulation. Km for pentagastrin alone was higher than previously found in unoperated duodenal ulcer patients.     

Regulation of fat-stimulated neurotensin secretion in healthy subjects

CONTEXT: Cholecystokinin (CCK) and neurotensin are stimulated during meal intake by the presence of fat in the small intestine. The sequence of events suggests that fat hydrolysis is crucial for triggering the release. OBJECTIVE: The aim of this study was to investigate whether CCK mediated the effect of intraduodenal (ID) fat on neurotensin secretion via CCK-1 receptors. SETTING: This was a single center study; 34 male volunteers were studied in consecutive, randomized, double-blind, cross-over studies. SUBJECTS AND METHODS: CCK and neurotensin release were quantified in: 1) 12 subjects receiving an ID fat infusion with or without 60 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison to vehicle; 2) 12 subjects receiving ID long chain fatty acids (C18s), ID medium chain fatty acids, or ID vehicle; and 3) 10 subjects receiving ID C18 with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). Hormone concentrations were measured by specific RIA systems. RESULTS: ID fat induced a significant increase in CCK and neurotensin concentrations (P < 0.001-0.002). Inhibition of fat hydrolysis by orlistat abolished both effects. C18 stimulated CCK and neurotensin release (P < 0.001, respectively), whereas medium chain fatty acid was ineffective. Dexloxiglumide administration partially blocked the effect of C18 on neurotensin; the effect was only present in the first phase of neurotensin secretion. CONCLUSIONS: Generation of C18 through hydrolysis of fat is a critical step for fat-induced stimulation of neurotensin in humans; the signal is in part mediated via CCK release and CCK-1 receptors.     

Salicylates increase insulin secretion in healthy obese subjects

CONTEXT: Conflicting results on the effects of salicylates on glucose tolerance in subjects with normal glucose tolerance or type 2 diabetes have been reported. OBJECTIVE: The objective of the study was to investigate the effects of a salicylate derivative (triflusal) on insulin sensitivity and insulin secretion. DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomized, crossover study with three treatment periods corresponding to two dose levels of triflusal and placebo in healthy obese subjects. MAIN OUTCOME MEASURES: Insulin sensitivity and insulin secretion, evaluated through frequently sampled iv glucose tolerance test that was performed after each treatment period, were measured. Insulin secretion was also evaluated in vitro in mice and human islets of Langerhans. RESULTS: The administration of triflusal led to decreased fasting serum glucose concentration in the study subjects. Insulin sensitivity did not significantly change after each treatment period. Insulin secretion, however, significantly increased in a dose-dependent fashion after each triflusal treatment period. The administration of 800 mum of the main triflusal metabolite to whole mice islets of Langerhans led to a sustained increase in intracellular calcium concentration level. This was followed by a significantly increase in insulin secretion. In human islets, 200 mum of 2-hydroxy-4-trifluoromethylbenzoic acid was sufficient to increase insulin release. CONCLUSIONS: The administration of a salicylate compound led to lowering of serum glucose concentration. We suggest that this effect was mediated through increased insulin secretion induced by salicylate directly on the beta-cell.     

Prolactin secretion in pubertal and adult male subjects

Prolactin, LH and FSH circadian secretion were studied in a group of 20 boys in various pubertal stages and in 13 normal male adults. Prolactin 24-hour integrated concentration was similar in all groups except in stage 2 boys, in which it was significantly higher with respect to stage 3-4 boys. This pattern was observed also for nocturnal, but not for diurnal concentration. As already described by other authors, LH showed and amplified circadian secretion in stage 2 and 3-4 boys, particularly during night time. FSH increase was less evident, and reached the peak 24-hour mean concentration in stage 2 subjects. Our results suggest that during puberty the hypothalamic pituitary system increases its activity not only with regard to gonadotropins but also to prolactin secretion.     

Interaction of glucagon and pentagastrin on pepsin secretion in healthy subjects

The effect of pentagastrin in step-wise increasing doses of 0 . 02, 2 . 0 and 20 nmol/kg/h (0 . 01, 1 . 0, and 10 . 0 micrograms/kg/h) on pepsin and acid secretion was studied in seven healthy subjects. The study was repeated on another day during infusion of glucagon in a dose of 103 pmol/kg/h (0 . 36 micrograms/kg/h) which results in plasma-glucagon concentrations comparable with those seen after a protein-rich meal. Pepsin output was maximal after 0 . 2 nmol/kg/h (0 . 1 microgram/kg/h) of pentagastrin and 20 nmol/kg/h (10 micrograms/kg/h) resulted in a marked decrease. The dose of pentagastrin required for half-maximal pepsin output was less than 0 . 1 nmol/kg/h (0 . 05 micrograms/kg/h). When the study was repeated during infusion of glucagon, the dose-response curve was shifted to the right. The highest pepsin output was obtained with 20 nmol/kg/h (10 micrograms/kg/h) of pentagastrin and D50 increased to well over 1 microgram/kg/h. The dose of pentagastrin required for half-maximal acid secretion was about 0 . 3 nmol/kg/h (0 . 15 micrograms/kg/h) indicating that the sensitivity of the chief cells to pentagastrin is more than three times that of the parietal cells.     

Comparison of the effects of endothelin-1 and -3 on secretion of pituitary hormones in healthy male volunteers.

The investigation was conducted to study the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on adrenocorticotropin (ACTH), cortisol and prolactin release in man. The design was a prospective placebo controlled double-blind study, including 7 healthy males studied on three occasions. After infusion of either 20 ng/min x kg ET-1, ET-3 or normal saline, venous blood samples were drawn 12 times for determination of ACTH, cortisol and prolactin during the pre- within- and postinfusion period. ET-1 infusion induced a significant increase of plasma ACTH (p< 0.009) and prolactin (p<0.0001) whereas cortisol levels increased without reaching significance (p<0.074). Infusion of ET-3 induced no changes in plasma levels of ACTH, cortisol or prolactin. The parallel increase of ACTH and prolactin induced by infusion of ET-1 could indicate an involvement of corticotropin-releasing hormone (CRH) in mediating the ET-1 effect on the HPA-axis in man. Whether this supports a possible role of ET-1 as a modulator of the hypothalamo-pituitary-adrenal (HPA) axis remains to be clarified.