Lack of melatonin effects on insulin action in normal rats

Despite a large number of studies, the role of melatonin on glucose metabolism is still controversial. The aim of the present work was to further characterize the effect of melatonin on insulin action during: i) intravenous insulin tolerance test performed at different times of the day using melatonin, a melatonin agonist (S-20304), a melatonin antagonist (S-20928) or in pinealectomized rats. ii) euglycemic-hyperinsulinemic clamp performed in melatonin agonist-treated as well as in pinealectomized rats. The fall in glycemia after the insulin injection was not significantly affected by melatonin and melatonin agonist (S-20304) at ZT6, nor by the melatonin antagonist (S-20928) at ZT13 nor in pinealectomized animals at ZT6 in comparison to their respective control. Acute treatment with S-20304 or chronic suppression of melatonin by pinealectomy did not significantly alter basal plasma glucose and insulin levels or hepatic glucose production and whole body or individual tissue glucose utilization. These data do not give support to a crucial role of melatonin on insulin action in normal rats.     

Oxidative stress in diabetic rats induced by streptozotocin: protective effects of melatonin

Two years after Kurt Schneider had finalised his thesis qualifying him as a lecturer at Cologne University, he completed his doctorate dissertation in philosophy, also at Cologne University. His advisor was Max Scheler. Schneider published the results of his researches in a short monograph. It appears that at this time Scheler's phenomenology began to influence psychiatry. However, Kurt Schneider made only passing references to Max Scheler in this regard. Nevertheless, Scheler's influence on Schneider remained noticeable even in his most famous book "Clinical Psychopathology". Years after their academic contacts, Scheler, on several occasions, asked Schneider's advice concerning his psychically disturbed son Wolfgang. Schneider's diagnosis amounted to a case of a severely psychopathic personality. He informed Max Scheler on this and, subsequently, Wolfgang Scheler was interdicted, i.e. legally incapacitated.     

Somnogenic and pyrogenic effects of interleukin-1beta and lipopolysaccharide in intact and vagotomized rats

The vagus nerve appears to serve a role in mediating peripheral immunologic influences on CNS processes. Previous work demonstrates that subdiaphragmatic vagotomy prevents or attenuates many of the behavioral and physiological responses to exogenous interleukin-1 (IL-1) or lipopolysaccharide (LPS). We determined whether the somnogenic effects of IL-1 and LPS were altered in vagotomized rats, and whether the effects of vagotomy on IL-1- and LPS-induced alterations in sleep would vary as a function of circadian phase. The data indicate that vagotomy does not influence the normal circadian patterns of sleep and wakefulness in untreated rats, or modify the pyrogenic or somnogenic effects of intracerebroventricular administration of IL-1. However, in unchallenged animals vagotomy reduces basal brain temperatures, increases delta wave amplitudes during slow-wave sleep (SWS), and induces a reduced rate of weight gain, gastric distension, and adrenal hypoplasia. Vagotomy attenuates the febrile effects of IL-1 during both light and dark phases, attenuated IL-1-induced sleep enhancement during the dark phase, and attenuated IL-1-induced increases in delta wave amplitudes within SWS during the light period. In LPS-treated rats, vagotomy attenuates the febrile and SWS responses to LPS after administration at light onset, but not after administration at dark onset. These results indicate that subdiaphragmatic vagotomy attenuates several of the somnogenic and pyrogenic effects of IL-1beta and LPS, although the effectiveness of the vagal transection in modulating these responses is influenced by circadian factors.     

Cardiovascular and renal effects of hypoxia in conscious carotid body-denervated rats

The contribution of peripheral arterial chemoreceptors to cardiovascular and renal responses to acute hypocapnic hypoxia is currently not well understood. We compared the effects of normobaric hypoxia on mean arterial blood pressure (MABP), heart rate, glomerular filtration rate (GFR), renal blood flow (RBF), and renal volume and electrolyte excretion in conscious unilaterally nephrectomized carotid body-denervated (n = 10) and sham-operated (n = 10) control rats. Thirty minutes of normobaric hypoxia (12.5% O2) resulted in significant reductions in arterial PO2 and PCO2 as well as decreases in MABP, GFR, RBF, and renal sodium, potassium, and water excretion. These effects occurred more rapidly and/or were significantly more pronounced in carotid body-denervated than in sham-operated rats. These data indicate that moderate acute hypocapnic hypoxia has profound effects on systemic and renal hemodynamics as well as on renal excretory function in conscious rats. We conclude that stimulation of the peripheral arterial chemoreceptors can partially offset the hypoxia-induced decreases in MABP, RBF, GFR, urine flow, and urinary sodium and potassium excretion, thereby helping to maintain cardiovascular as well as fluid and electrolyte homeostasis.     

Differential effects of pharmacological doses of melatonin on malondialdehyde and glutathione levels in young and old rats

BACKGROUND: The free radical theory of aging suggests the oxygen-derived species as the causative agents and free radical scavengers as the defense systems in aging process. The exact role of the free radical scavenging effects of melatonin in aging remains to be clarified. OBJECTIVE: In this experimental study, we investigated the age-related changes of malondialdehyde (MDA), a lipid peroxidation product, and glutathione (GSH) and the effects of exogenous melatonin. METHODS: Plasma, liver, and lung MDA and GSH levels of 9- and 28-month-old rats were measured. RESULTS: Plasma, lung, and liver MDA levels of old rats were significantly higher than those of the young ones (p = 0.024, p = 0.005, and p = 0.0007, respectively). However, while the lung GSH levels were found to be significantly decreased in the control group of old rats as compared with young ones (p = 0.005), the liver GSH levels were unchanged. Plasma MDA levels were found to be significantly lower in the melatonin group of old rats as compared with the control group (p = 0.020) but lung and liver MDA levels were not significantly different. There were no significant differences in the levels of measured parameters between both groups of young rats. CONCLUSION: Our results suggest that increased levels of lipid peroxidation products may have a role in aging, and exogenous melatonin may delay the aging process of tissues by means of its free radical scavenging effects.     

The effects of strychnine, bicuculline, and ketamine on ''immersion-inhibited'' dorsal horn convergent neurons in intact and spinalized rats

Dinucleoside(5',5') polyphosphates (ApnA, ApnG, GpnG, n=3-6) are new group of hormones controlling important biological processes. Because some of the dinucleoside(5',5') polyphosphates are commercially not available purification of chemical synthesised dinucleoside(5',5') polyphosphates became necessary in order to test their physiological and pharmacological properties. It was the aim of this study to find a method which allows purification of 0.1-0.2 g quantities of dinucleoside polyphosphates by analytical HPLC columns yielding products with impurities lower than 1.0%. Adenosine(5')-polyphospho-(5')guanosines were synthesised by mixing the corresponding mononucleotides. The reaction results in a complex mixture of ApnA, ApnG and GpnG (with n=3-6 in all cases). The reaction mixture was concentrated on a preparative C18 reversed-phase column. The concentrate was displaced on a reversed-phase stationary. As a result of displacement chromatography, anion-exchange chromatography in gradient modus yielded baseline separated dinucleoside polyphosphates (homogeneity of the fractions>99%). The identity of the substances were determined by matrix assisted laser desorption ionisation mass spectrometry.     

Presence of melatonin in plasma and urine or pinealectomized rats

Melatonin was shown to occur in rat plasma and urine after pinealectomy by bioassay, radioimmunoassay, and thin-layer chromatography. Total daily excretion of melatonin in pinealectomized rats was about 20% of control. Light-dark rhythms of plasma melatonin levels and urinary excretion rates disappeared after pinealectomy.     

Inhibitory effects of procainamide and probenecid on renal excretion of sultopride enantiomers in rats

The effects of the coadministration of procainamide and probenecid on the pharmacokinetic behavior of sultopride, an antipsychotic agent, after intravenous administration were studied with rats. The areas under the concentration-time curve for and renal clearances of (+)-sultopride and (-)-sultopride, which exist as organic cations under physiological pH conditions, were significantly decreased (p < 0.01) by the coadministration of procainamide, an organic cation under physiological pH conditions. The renal clearance of (-)-sultopride was partially decreased (p < 0.05) by the coadministration of probenecid, an organic anion under physiological pH conditions. The results suggest that drug-drug interactions between organic cations and organic anions occur to a certain extent during the tubular secretion process in rats.     

Effect of continuous melatonin infusions on steady-state plasma melatonin levels in rats under near physiological conditions

Over one hundred cases of legionnaires' disease have been linked to ships, and ten cases are known to have died. Most of the cases were associated with cruise ships, but a variety of other vessels were also linked to cases. Few vessels were investigated microbiologically, and the cases associated with ferries were exposed to other sources of infection. Cases appear to be less common among crew members than among passengers. To prevent further cases, ship owners, operators, and captains need to be diligent in maintaining the water and air conditioning systems of their vessels. Whirlpool spas need particular care. Ship-associated cases of non-pneumonic legionellosis appear to be rare.     

Inconsistent suppression of nocturnal pineal melatonin synthesis and serum melatonin levels in rats exposed to pulsed DC magnetic fields

The purpose of these experiments was to determine whether the exposure of rats at night to pulsed DC magnetic fields (MF) would influence the nocturnal production and secretion of melatonin, as indicated by pineal N-acetyltransferase (NAT) activity (the rate limiting enzyme in melatonin production) and pineal and serum melatonin levels. By using a computer-driven exposure system, 15 experiments were conducted. MF exposure onset was always during the night, with the duration of exposure varying from 15 to 120 min. A variety of field strengths, ranging from 50 to 500 microT (0.5 to 5.0 G) were used with the bulk of the studies being conducted using a 100 microT (1.0 G) field. During the interval of DC MF exposure, the field was turned on and off at 1-s intervals with a rise/fall time constant of 5 ms. Because the studies were performed during the night, all procedures were carried out under weak red light (intensity of <5 microW/cm2). At the conclusion of each study, a blood sample and the pineal gland were collected for analysis of serum melatonin titers and pineal NAT and melatonin levels. The outcome of individual studies varied. Of the 23 cases in which pineal NAT activity, pineal melatonin, and serum melatonin levels were measured, the following results were obtained; in 5 cases (21.7%) pineal NAT activity was depressed, in 2 cases (8.7%) studies pineal melatonin levels were lowered, and in 10 cases (43.5%) serum melatonin concentrations were reduced. Never was there a measured rise in any of the end points that were considered in this study. The magnitudes of the reductions were not correlated with field strength (i.e., no dose-response relationships were apparent), and likewise the reductions could not be correlated with the season of the year (experiments conducted at 12-month intervals under identical exposure conditions yielded different results). Duration of exposure also seemed not to be a factor in the degree of melatonin suppression. The inconsistency of the results does not permit the conclusion that pineal melatonin production or release are routinely influenced by pulsed DC MF exposure. In the current series of studies, a suppression of serum melatonin sometimes occurred in the absence of any apparent change in the synthesis of this indoleamine within the pineal gland (no alteration in either pineal NAT activity or pineal melatonin levels). Because melatonin is a direct free radical scavenger, the drop in serum melatonin could theoretically be explained by an increased uptake of melatonin by tissues that were experiencing augmented levels of free radicals as a consequence of MF exposure. This hypothetical possibly requires additional experimental documentation.     

Sigma receptor modulation of noradrenergic-stimulated pineal melatonin biosynthesis in rats

Because sigma receptors are richly concentrated in the rat pineal gland, the present study was performed to investigate their possible role in the modulation of melatonin production. To this purpose, we assessed in vivo the effects of the sigma-receptor ligands 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine on the rat pineal gland activity during either the daytime or the nighttime. Compared with vehicle, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine potentiated the enhancement of N-acetyltransferase activity and pineal melatonin content induced by isoproterenol administration during the daytime, whereas they did not affect the diurnal basal biosynthetic activity of the gland. Conversely, at night, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine enhanced significantly the physiological increases in both pineal N-acetyltransferase activity and melatonin levels. This enhancement was prevented by pretreatment with rimcazole, a specific sigma-receptor antagonist. These findings suggest that, in rats, the activation of pineal sigma-receptor sites does not affect the biosynthetic activity of the pineal gland during daytime, whereas it potentiates the production of melatonin when the gland is noradrenergically stimulated either by isoproterenol administration or by the endogenously released norepinephrine at nighttime.     

Central effect of melatonin against stress-induced gastric ulcers in rats

We investigated the role of melatonin in the induction of gastric lesions induced by water immersion restraint stress or centrally administered thyrotropin-releasing hormone (TRH). Melatonin (0.1-1 ng) injected intracisternally (i.c) 30 min prior to stress dose-dependently inhibited the induction of gastric lesions by water immersion restraint stress, while 100 micrograms/kg, i.p. failed to protect the gastric mucosa. Preadministration of melatonin (1 ng, i.c.) significantly reduced (83%) the severity of gastric lesions induced by a TRH analogue (500 ng, i.c.). Serum melatonin concentrations 30 min after administration of 1 ng melatonin i.c. did not differ from those of rats receiving i.c. vehicle. These results suggest that melatonin plays a protective, anti-stress, role in the gastric mucosa via a mechanism involving the central nervous system.     

Daily caloric intake in intact and chronic decerebrate rats.

Daily caloric intake regulation was studied in chronic supracollicular decerebrate rats with a complete transaction of the neural axis at the meso–diencephalic juncture and in intact controls. For 1 wk, each rat received 3 intraorally delivered meals per day. They were challenged to maintain their 3-meal daily intake over 1 wk, in which only 2 meals per day were delivered. Intact rats increased meal size to compensate for the lost opportunity to feed, whereas chronic decerebrate rats did not. Results suggest that, although the caudal brain stem, as previously shown (H. J. Grill and J. M. Kaplan, 1990), is sufficient to modulate ingestive behavior in taste reactivity and single-meal tests, it is not sufficient to regulate daily caloric intake. Although it is possible that chronic decerebrate rats retain a long-term regulatory competence that is somehow masked under the meal omission paradigm, forebrain–hindbrain interactions appear necessary for the coordination of short- and long-term control processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Scanning electron microscopy of penile papillae in intact and castrated rats

Oviduct segments from infundibulum, magnum, uterus, utero-vaginal junction and vagina of actively laying hens at preoviposition time were tested for their contractile reaction to prostaglandin E1 by in vitro or in vivo methods. Maximum stimulatory response was observed from the muscular strips of the proximal oviduct segment (infundibulum) and a complete relaxation was recorded from the distal part (vagina) at molar concentrations of 1.4 X 10(-7), 3.4 X 10(-7) and 7.0 X 10(-7). The uterine strips reacted with a stimulatory response at higher concentrations (1.4 X 10(-6) and 2.8 X 10(-6) moles), but lacked any significant change at lower concentrations. The uterovaginal muscular strips showed a mild but prolonged inhibitory response, while the magnum responded with a significant increase in the luminal pressure when tested in vivo. It is concluded that PGE1 exerts a stimulatory effect on the uterus to initiate transport of the egg to subsequent segments (utero-vaginal junction and vagina), which relax under PGE1 influence and allow passage of the egg by pressure differences.     

Effect of melatonin on 1,2-dimethylhydrazine-induced intestinal tumors in rats

Fifteen doses of 21 mg/kg body weight of 1,2-dimethylhydrazine (DMH) were injected into 48 female rats at one-week intervals. Controls included 25 animals while 23 received 20 mg/l of melatonin with drinking water, 5 times a week, at night-time, for 6 months, beginning from the day of the first injection. Although malignancies of large bowel developed in all animals, multiple tumors in the melatonin group were significantly fewer than in the rats treated with DMH alone (6,0 and 9,9 respectively; p < 0,001). Similarly, melatonin treatment was followed by a significantly lower frequency of tumor development in the ascending colon as well as fewer multiple neoplasms of the ascending and descending colon. Melatonin was also shown to inhibit carcinogenesis in the small intestine. It is suggested that the antitumor effects of melatonin is due to its antioxidant properties.     

Renal effects of a high unsaturated fat diet in renal artery stenosis in rats

The in vitro effect of prolactin (PRL) on protein phosphorylation in male guinea pig adrenal cortex has been studied. It was found that 60 min after addition of PRL (10 micrograms/ml) to slices of adrenocortical tissue the rate of protein phosphorylation increased considerably. Autoradiographic studies revealed that at least part of the proteins are substrates for protein kinase C, since their phosphorylation increased in the presence of specific activators of protein kinase C (Ca2+, diacylglycerol, phosphatidyl serine) in the incubation medium. The molecular masses of these proteins were 95, 93, 90, 12 and 10 kDa. In extracts of PRL-treated adrenocortical tissue phosphorylation of these proteins was especially well-pronounced. Addition of staurosporine (10 nM) during incubation of the slices abolished the PRL effect on protein phosphorylation without any effect on the rate of unstimulated phosphorylation. Taking into account the ability of isolated nuclei to respond to PRL by activation of protein kinase C, the time course of PRL stimulation of protein phosphorylation was studied using preparations of isolated nuclei. The maximal increase of 32P incorporation into the proteins from [gamma-32P]ATP was observed after 60 min. Staurosporine only slightly attenuated the PRL effect.     

The effects of N-benzoyl-beta-alanine, a new nephroprotective drug, on the distribution and renal excretion of enprofylline in rats

The effects of the new nephroprotective drug N-benzoyl-beta-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2.5 mg kg-1 under three different steady-state plasma BA concentrations (100, 200 and 400 micrograms mL-1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 micrograms mL-1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 micrograms mL-1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

Diversity in the renal hemodynamic effects of dihydropyridine calcium blockers in spontaneously hypertensive rats

BACKGROUND: Death rates from coronary hearts disease have exhibited remarkable declines in most industrialised countries. Cardiovascular mortality has been the subject of extensive research and we considered it important to analyse recent local population based data on hospital outcomes of acute myocardial infarction (AMI). AIM: To document the trends in in-hospital mortality from AMI in Victoria from 1987-1994. METHODS: This was a retrospective analysis of data from the Victorian Inpatient Minimum Database relating to all public acute care hospitals. All separations recording a principal diagnosis 410 (AMI) were selected. Changes in distribution of AMI separations, in-hospital mortality, and changes in length of stay were examined. RESULTS: The mean age of women admitted was 72 years compared with 64 years for men. Women comprised around a third of the overall sample but the proportion varied from 13% in those under 50 years to 57% among those aged 80 years and over. A striking decline in mortality was observed throughout the eight year period. The relative age adjusted decline was 33.5% (40% in males and 26% in females) with rates remaining higher in women. This decline occurred despite the increasing representation of those aged over 80 years. There was a significant decline in the mean length of stay (1.8 days) over the eight year period but this is likely to have had only minimal impact on mortality rates. CONCLUSION: We have documented welcome declines in in-hospital mortality from AMI that are not an artefact of declining lengths of stay. Our observations parallel those in similar overseas studies. Large changes in medical management have taken place from the mid 1980s and may be partly responsible, but a change in disease process cannot be ruled out.