Ewa Bojanowska

Effects of centrally or systemically injected glucagon-like peptide-1 (7–36) amide on release of neurohypophysial hormones and blood pressure in the rat

The present study was designed to compare the effects of glucagon-like peptide-1 (7-36) amide (GLP-1) injected centrally or systemically in a dose range of 10-10000 ng on the vasopressin and oxytocin release as well as the blood pressure in the rat. The urethane-anaesthetised Wistar male and female rats were fitted with venous as well as arterial catheters and, in the second study, additionally with the intracerebroventricular cannula. The arterial blood pressure was monitored throughout the experiment. The plasma vasopressin/oxytocin concentrations were measured in blood samples taken 15 min before and 5, 15 and 30 min after the intravenous or intracerebroventricular GLP-1 injection. No gender-dependent differences were seen as to the GLP-1 effect on the blood pressure or the hormone release. GLP-1 administered centrally or systemically at low doses (10 or 100 ng) either showed a hypertensive or biphasic (an increase followed by a decrease in the blood pressure) effect. On the other hand, 1000 or 10000 ng GLP-1 caused a clear increase of the blood pressure regarding the way of injection. When injected systemically, GLP-1 increased the release of both neurohypophysial hormones. When injected centrally, however, GLP-1 either enhanced or, at low doses, significantly reduced the plasma vasopressin/oxytocin levels. The effect on the blood pressure seems to be independent of the possible pressor effect of endogenous vasopressin. It is concluded that GLP-1 may modulate the function of the hypothalamo-neurohypophysial system as well as the cardiovascular system through both the central and systemic mechanisms.

The effects of melatonin on vasopressin secretion in vivo: interactions with acetylcholine and prostaglandins.

The pineal hormone melatonin influences the neurohypophysial hormone release from the isolated hypothalamus in vitro through the effect on the cholinergic pathways as well as the biosynthesis of prostaglandins. The aim of the present study was, therefore, to investigate the effects of melatonin (0.5, 1, or 5 ng) administered in vivo on the vasopressin and oxytocin release as well as to examine whether similar interactions between melatonin and acetylcholine or prostaglandins occur in vivo. In the initial study on the effect of melatonin male Sprague-Dawley rats were implanted under anaesthesia with an arterial and venous cannula. Melatonin in a dose of 0.5 ng injected intravenously had no effect on plasma vasopressin concentration. The higher dose of 1 ng caused a significant decrease in vasopressin release 10 min after injection, whereas 5 ng melatonin caused an increase in plasma hormone concentrations, the difference being significant 20 min after injection. No significant effects of melatonin on the oxytocin release was found. In the second study in which an I.C.V. cannula was additionally implanted, the cholinergic muscarinic receptor antagonist atropine (10 microg) injected I.C.V. abolished the melatonin-induced effects on plasma vasopressin level. On the other hand, a cyclo-oxygenase inhibitor ibuprofen (75 microg) injected I.C.V. blocked the vasopressin release induced by 5 ng melatonin and reversed the inhibitory effect of 1 ng melatonin. These results demonstrate that melatonin affects the neurosecretory function of the hypothalamo-neurohypophysial complex in vivo possibly via mechanisms involving cholinergic transmission and/or prostaglandin biosynthesis.

Luteinizing hormone-releasing hormone and function of the magnocellular vasopressinergic system

Mechanisms by which luteinizing hormone-releasing hormone (LHRH) affects vasopressin secretion were investigated using the isolated rat hypothalamo-neurohypophysial explants. LHRH in a concentration of 4 x 10(-7)M inhibited both the basal and K(+)-stimulated vasopressin release from explants isolated from euhydrated rats. When, however, the tissue was obtained from animals previously salt-loaded, the inhibitory effect of LHRH was completely abolished, thus implying a decrease in the sensitivity to LHRH. LHRH did not affect vasopressin secretion under conditions of generalized blockade of synaptic inputs by 15 mM MgSO(4), suggesting the indirect action of this neurohormone on the hypothalamic magnocellular system. It is concluded that LHRH may play the role of a neuromodulator of vasopressinergic neurones in the rat.

Melatonin and the Synthesis of Vasopressin in Pinealectomized Male Rats

The pineal hormone, melatonin, is known to modify, under different experimental conditions, neurohypophysial hormone secretion in the rat. The aim of this study was to investigate the effect of melatonin on the vasopressin biosynthesis rate in the hypothalamus of either pinealectomized or sham-operated rats, using the colchicine method. To estimate whether colchicine affects the function of the neurohypophysis in these animals, the neurohypophysial and plasma vasopressin levels were also measured. The vasopressin synthesis rate was increased after pineal removal, when compared with sham-operated animals, and melatonin strongly inhibited the rise in the hormone synthesis due to pinealectomy. After pineal removal plasma vasopressin concentration was significantly elevated, and melatonin attenuated this effect. On the contrary, the neurohypophysial vasopressin content was significantly decreased after pinealectomy, but it was not further modified by melatonin.Thus, melatonin suppresses the synthesis and secretion of vasopressin in pinealectomized rats. The present results confirm our previous reports as to the inhibitory impact of the pineal on both vasopressin synthesis and release and suggest that melatonin may mediate the effect of the pineal gland on vasopressinergic neuron activity.

Luteinizing hormone-releasing hormone and oxytocin response to hyperosmotic stimulation: in vitro study.

It was shown previously that luteinizing hormone-releasing hormone (LHRH) affects the neurohypophysial oxytocin release in water-deprived rats. However, the detailed mechanisms by which LHRH modifies the oxytocin response to hyperosmotic stimulation have not been explained so far. Using the isolated hypothalamo-neurohypophysial explants obtained from euhydrated rats, the effect of LHRH on the oxytocin secretion was studied under conditions of direct osmotic (i.e., Na(+)- evoked) as well as nonosmotic (i.e., K(+)-evoked) stimulation. Additionally, the oxytocin response to LHRH was investigated using the explants obtained from animals drinking 2% saline for eight days (systemic, i. e., both direct and indirect, osmotic stimulation). LHRH significantly enhanced Na(+)- and K(+)-evoked oxytocin release from explants taken from rats drinking tap water, indicating that LHRH could affect the Na(+)/K(+)-dependent depolarization of perikarya of oxytocin neurones. In contrast, LHRH significantly diminished the K(+)-stimulated hormone release when the neurohypophysial complex was obtained from previously salt-loaded rats, suggesting that peripheral osmotic stimulation somehow modifies the sensitivity of oxytocinergic neurones to LHRH (possible mechanisms are discussed). It is concluded that LHRH may participate in the regulation of oxytocin secretion via both direct and indirect impact on magnocellular oxytocinergic neurones depending on the current functional status of the hypothalamo-neurohypophysial complex.

Can We Selectively Reduce Appetite for Energy-Dense Foods? An Overview of Pharmacological Strategies for Modification of Food Preference Behavior

Excessive intake of food, especially palatable and energy-dense carbohydrates and fats, is largely responsible for the growing incidence of obesity worldwide. Although there are a number of candidate antiobesity drugs, only a few of them have been proven able to inhibit appetite for palatable foods without the concurrent reduction in regular food consumption. In this review, we discuss the interrelationships between homeostatic and hedonic food intake control mechanisms in promoting overeating with palatable foods and assess the potential usefulness of systemically administered pharmaceuticals that impinge on the endogenous cannabinoid, opioid, aminergic, cholinergic, and peptidergic systems in the modification of food preference behavior. Also, certain dietary supplements with the potency to reduce specifically palatable food intake are presented. Based on human and animal studies, we indicate the most promising therapies and agents that influence the effectiveness of appetite-modifying drugs. It should be stressed, however, that most of the data included in our review come from preclinical studies; therefore, further investigations aimed at confirming the effectiveness and safety of the aforementioned medications in the treatment of obese humans are necessary.

Neurohypophysial response to haemorrhage or dehydration: interactions of vasopressin and luliberin

Abstract Rats, euhydrated, dehydrated for two days or haemorrhaged, were given intracerebroventricularly (i.c.v.) luteinizing hormone releasing hormone (LH-RH) in a daily dose of 100 ng dissolved in 10 μl of 0.9% sodium chloride. In euhydrated rats, a single dose of LH-RH as well as the daily i.c.v. treatment with LH-RH over two days did not significantly affect either the plasma vasopressin concentrations or hypothalamo-neurohypophysial vasopressin content. On haemorrhage (1 ml per 100 g), the increase in plasma vasopressin was almost inhibited and the depletion of neurohypophysial hormone content significantly diminished in animals previously treated with LH-RH. Similarly, LH-RH attenuated markedly the enhanced vasopressin release from the hypothalamo-neurohypophysial system brought about by two-day dehydration. We suggest that LH-RH may have a regulatory role in the hypothalamo-neurohypophysial system especially under conditions of haemorrhage or hyperosmotic dehydration.

Concurrent pharmacological modification of cannabinoid-1 and glucagon-like peptide-1 receptor activity affects feeding behavior and body weight in rats fed a free-choice, high-carbohydrate diet.

To extend preliminary studies on the effects on food intake of the combined use of cannabinoid (CB) 1 and glucagon-like peptide-1 (GLP-1) receptor agonists and antagonists, the effect of these drugs on the feeding behavior in rats maintained on a free-choice, high-carbohydrate diet was investigated over a longer period of time. Rats were fed a standard diet for 3 days and then fed with both the standard and the high-sucrose chow. After 4 days of the high-calorie diet, the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days: 1 mg/kg AM 251 (a CB1 receptor antagonist) or 1 mg/kg WIN 55,212-2 (a CB1 receptor agonist) together with 3 µg/kg exendin-4 (Ex-4, a GLP-1 receptor agonist) or 160 µg/kg exendin (9-39) [Ex (9-39), a GLP-1 receptor antagonist]. The total daily caloric intake and body weight were significantly reduced in rats treated with Ex-4 and AM 251 or WIN 55,212-2 compared with either of the drugs injected alone and the saline-injected controls. Both drug combinations selectively inhibited ingestion of the high-sucrose chow. Although Ex (9-39) administration did not significantly affect food consumption, it resulted in a marked body weight gain, indicating that the GLP-1 receptor antagonist caused a positive energy balance. It is concluded that AM 251 or WIN 55,212-2 and Ex-4, injected together, exert additive, inhibitory effects on the consumption of high-sugar food.

Effects of glucagon-like peptide-1 (7–36) amide on neurohypophysial hormone secretion induced by acute hyperosmotic challenge☆

This study was designed to investigate possible effects of glucagon-like peptide-1 (7-36) amide on the vasopressin and oxytocin release induced by acute peripheral or central osmotic stimulation. In the first series of experiments, rats were injected intraperitoneally with the isotonic (0.15 M) or hypertonic (1.5 M) NaCl solution and then, intracerebroventricularly, with either 1 microg glucagon-like peptide-1 (7-36) amide dissolved in 5 microl of isotonic saline or with the vehicle only. In the second study, 1 microg glucagon-like peptide-1 (7-36) amide, dissolved in isotonic or hypertonic (0.6 M) saline, was injected into the cerebroventricular system. Control rats were treated with isotonic or hypertonic saline only. All the animals were decapitated 10 min after the intracerebroventricular injection. Glucagon-like peptide-1 (7-36) amide enhanced significantly the basal secretion of vasopressin and oxytocin. Moreover, this peptide increased additionally the release of both neurohypophysial hormones stimulated previously by peripheral osmotic challenge. On the other hand, the peptide increased the oxytocin but not vasopressin secretion brought about by an intracerebroventricular injection of hypertonic saline thus suggesting that the central osmotic stimulation decreases the sensitivity of vasopressin neurons to glucagon-like peptide-1 (7-36) amide. It is concluded that glucagon-like peptide-1 (7-36) amide may affect the secretory activity of the hypothalamo-neurohypophysial system under acute osmotic challenge.

The role of histamine in the regulation of the viability, proliferation and transforming growth factor β1 secretion of rat wound fibroblasts

BACKGROUND Inflammation mediators play a regulatory role in repair processes. The study will examine the influence of histamine on wound fibroblast metabolic activity, viability, proliferation, and TGFβ1 secretion. The study also will identify the histamine receptor involved in regulation of the tested repair processes. METHODS Fibroblasts were obtained from the granulation tissue of wounds or intact dermis of rats. The MTT and BrdU assays were used to examine the effect of histamine (10-8M-10-4M) on the viability and metabolic activity of fibroblasts, and on their proliferative capacity. The influence of histamine receptor antagonists (i.e., ketotifen, ranitidine, ciproxifan and JNJ7777120) and agonists (2-pyridylethlamine dihydrochloride, amthamine dihydrobromide) was also investigated. The TGFβ1 and histamine receptors H1 were evaluated by enzyme-linked immunosorbent assay. RESULTS Histamine significantly increased granulation tissue fibroblast viability and metabolic activity at 10-8 and 10-6M but did not change their proliferative activity. Only the blockade of the H1 receptor removed this effect of histamine. H1 receptor agonist (2-pyridylethlamine dihydrochloride) increased cell viability, thereby mimicking histamine action. Both Histamine (10-4M) and 2-pyridylethlamine dihydrochloride increased TGFβ1 concentration in cell culture medium. However, ketotifen blocked histamine-induced augmentation of TGFβ1. H1 receptor expression on wound fibroblasts was confirmed. CONCLUSION The regulatory influence of histamine on wound fibroblast function (viability/metabolic activity or secretion of TGFβ1) is dependent on H1 receptor stimulation. Contrary to wound fibroblasts, these cells express a very low level of H1 receptors when isolated from intact dermis and histamine is unable to modify their metabolic activity.