Guldal Gulec

Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin.

We aimed to investigate the effects of intracerebroventricularly (i.c.v.) injected glucagon-like peptide-1 (GLP-1) on blood pressure and heart rate, and whether central cholinergic system and vasopressinergic system play roles in these effects. Male Wistar albino rats were used throughout the experiments. Blood pressures and heart rates were observed before and for 30 min following drug injections. i.c.v. GLP-1 (100, 500 and 1000 ng/10 microl) caused a dose-dependent increase in both blood pressure and heart rate. Nicotinic receptor antagonist mecamylamine (25 microg/10 microl, i.c.v.) and muscarinic receptor antagonist atropine (5 microg/10 microl, i.c.v.) prevented the stimulating effect of GLP-1 on blood pressure. The effect of GLP-1 on heart rate was blocked only by mecamylamine. The V1 receptor antagonist of vasopressin (B-mercapto B, B-cyclopentamethylenepropionyl, O-Me-Tyr,Arg)-vasopressin (10 microg/kg), that was applied intraarterially, only prevented the effect of GLP-1 on blood pressure, but did not show any effect on heart rate. Our data indicate that i.c.v. GLP-1 increases blood pressure and heart rate, and stimulation of central nicotinic and partially muscarinic receptors and vasopressinergic system play a role in the effects of i.c.v. GLP-1 on blood pressure. The effect of GLP-1 on heart rate may be partially due to stimulation of central nicotinic receptors.

Effects of intracerebroventricularly-injected morphine on anxiety, memory retrieval and locomotor activity in rats: involvement of vasopressinergic system and nitric oxide pathway.

Morphine has been shown to alter several behavioural processes. We aimed to investigate the effects of intracerebroventricular (i.c.v.) morphine on anxiety, memory retrieval and locomotor activity in rats and to elucidate the possible involvement of the vasopressinergic system and the nitric oxide (NO) pathway in these effects. Rats were pretreated with morphine (0.5, 5, 50 microg/5 microl; i.c.v.) or saline (5 microl; i.c.v.) 30 min before the elevated plus maze test, the probe trial of the Morris water maze and the open field test. Morphine (5 microg/5 microl; i.c.v.) induced significant anxiolytic effects in the elevated plus maze. None of the doses of morphine produced any effects in the probe trial of the Morris water maze and the open field. Pretreatment with an arginine vasopressin (AVP) V(1) receptor antagonist (25, 125 ng/5 microl; i.c.v.), an AVP V(2) receptor antagonist (25, 125 ng/5 microl; i.c.v.), or L-NAME, an NO synthase inhibitor (5, 25 microg/5 microl; i.c.v.) 30 min before morphine significantly prevented the anxiolytic effects of morphine. These results suggest that i.c.v. morphine has significant anxiolytic effects, probably mediated by both vasopressinergic system and NO pathway, but has no effect on memory retrieval or locomotor activity, at least at the applied doses.

Do recurrent febrile convulsions decrease the threshold for pilocarpine-induced seizures? Effects of nitric oxide.

The aim of the study was to determine whether (1) number of febrile convulsions is a predictor of development of temporal lobe epilepsy, (2) the susceptibility of rats to pilocarpine-induced seizures is increased due to febrile convulsions and (3) nitric oxide is a mediator in the pathogenesis of febrile convulsions. Rat pups were exposed to single or multiple hyperthermic seizures. Subconvulsant doses of pilocarpine (100 mg/kg and 150 mg/kg) were injected intraperitoneally to these rats at 60--70 days of age. Also L-arginine was applied to some rats before a single hyperthermic seizure. We found that risk of future epilepsy increases parallel to the number of febrile convulsions and nitric oxide does not have a pathogenetic role at given doses.

Effects of centrally-injected glucagon-like peptide-1 on pilocarpine-induced seizures, anxiety and locomotor and exploratory activity in rat.

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is a gut peptide, which exerts significant effects on glucose homeostasis. GLP-1 and GLP-1 receptors are also widely distributed in the central nervous system. In the present study, we aimed to investigate the effects of intracerebroventricularly (i.c.v.)-injected GLP-1 on pilocarpine-induced seizures, anxiety and locomotor and exploratory activity in rat. Rats were pretreated with GLP-1 (1-1000 ng/5 microl; i.c.v.) or saline (5 microl; i.c.v.) 30 min before seizure induction by pilocarpine (2.4 mg/5 microl; i.c.v.) and with GLP-1 (1, 10, 100 ng/5 microl; i.c.v.) or saline (5 microl; i.c.v.) 30 min before the open field test or the elevated plus maze test. GLP-1 did not produce any protective effect against pilocarpine-induced seizures and did not also produce statistically significant differences in the number of squares visited (measure of locomotor activity) or number of rearings (measure of exploratory behaviour), compared to the saline-treated rats in the open field test. On the other hand, GLP-1 (1 ng and 10 ng; i.c.v.) induced an anxiogenic effect, indicated by a decrease in the time spent in open arms, an increase in the time spent in closed arms, and a decrease in the anxiety scores in the elevated plus maze test. Pretreatment with an arginine vasopressin (AVP) V(1) receptor antagonist (125 ng/5 microl; i.c.v.) and L-NAME (100 microg/5 microl and 200 microg/5 microl) significantly abolished the anxiogenic effect of GLP-1 (1 ng/5 microl; i.c.v.). These results suggest that, centrally-injected GLP-1 produces anxiogenic effects via NO pathway and AVP V(1) receptors, but does not have any effects on pilocarpine-induced seizures or locomotor and exploratory activity in the open field test.

Investigation of the mechanisms involved in the central effects of glucagon-like peptide-1 on ethanol-induced gastric mucosal lesions

The aim of this study was to investigate the effects of intracerebroventricularly injected glucagon-like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and to elucidate the mechanisms involved. Absolute ethanol was administered through an orogastric cannula 5 min before GLP-1 (1 microg/10 microl) injection. One hour later, the rats were decapitated, their stomachs were removed and scored for mucosal damage. GLP-1 inhibited the ethanol-induced gastric mucosal damage by 92%. Centrally injected atropine sulphate, a muscarinic receptor antagonist (5 microg/10 microl), prevented the gastroprotective effect of GLP-1, while mecamylamine, a nicotinic receptor antagonist (25 microg/10 microl), was ineffective. Peripherally injected atropine methyl nitrate (1 mg/kg) did not change the effect of GLP-1, but mecamylamine (5 mg/kg) blocked it. Cysteamine, a somatostatin depletor (280 mg/kg, s.c.), did not affect the protective activity of GLP-1, while inhibition of nitric oxide (NO) synthesis by L-NAME (3 mg/kg, i.v.) significantly abolished the protective effect of GLP-1 on ethanol-induced gastric mucosal lesions. We conclude that central muscarinic and peripheral nicotinic cholinergic receptors and NO, but not somatostatin, contribute to the protective effect of intracerebroventricularly injected GLP-1 on ethanol-induced gastric mucosal damage.

Effects of centrally injected GLP-1 in various experimental models of gastric mucosal damage.

Glucagon-like peptide-1 (GLP-1) is accepted to be a peptide involved in the central regulation of gastrointestinal function, but its potential gastroprotective effect is not clear. The aim of this study was to investigate whether intracerebroventricularly injected GLP-1 has protective effects on gastric mucosal lesions induced by several models, and if yes, whether these effects are due to the gastric antisecretory effect of the peptide. GLP-1 which was injected in three different doses (1, 10, 100 ng/10 microl; i.c.v.) to conscious rats prevented the mucosal lesions induced by reserpine and ethanol, but did not prevent the gastric mucosal lesions induced by pyloric ligation. In addition, 1 ng/10 microl dose of centrally injected GLP-1 inhibited gastric acid secretion in pylorus-ligated rats. As a result, we conclude that intracerebroventricularly injected GLP-1 may play a role in the prevention of gastric mucosal lesions induced by certain experimental models and this gastroprotective effect may be independent from its antisecretory effect.

Central injection of captopril inhibits the blood pressure response to intracerebroventricular choline

In the present study, we investigated the involvement of the brain renin-angiotensin system in the effects of central cholinergic stimulation on blood pressure in conscious, freely moving normotensive rats. In the first step, we determined the effects of intracerebroventricular (icv) choline (50, 100 and 150 microg) on blood pressure. Choline increased blood pressure in a dose-dependent manner. In order to investigate the effects of brain renin-angiotensin system blockade on blood pressure increase induced by choline (150 microg, icv), an angiotensin-converting enzyme inhibitor, captopril (25 and 50 microg, icv), was administered 3 min before choline. Twenty-five microg captopril did not block the pressor effect of choline, while 50 microg captopril blocked it significantly. Our results suggest that the central renin-angiotensin system may participate in the increase in blood pressure induced by icv choline in normotensive rats.

Peripheral GLP-1 gastroprotection against ethanol: the role of exendin, NO, CGRP, prostaglandins and blood flow.

The aim of this study was to investigate the effects of peripherally injected glucagon like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and the mechanisms included in the effect. Absolute ethanol was administered through an orogastric cannula right after the injection of GLP-1 (1, 10, 100, 1000 or 10,000 ng/kg; i.p.). The rats were decapitated an hour later, the stomachs removed and the gastric mucosal damage scored. 1000 ng GLP-1 inhibited gastric mucosal damage by 45% and 10,000 ng GLP-1 by 60%. The specific receptor antagonist exendin-(9-39) (2500 ng/kg; i.p.), calcitonin gene related peptide (CGRP) receptor antagonist CGRP-(8-37) (10 microg/kg; i.p.), nitric oxide (NO) synthase inhibitor l-NAME (30 mg/kg; s.c.) and cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.) inhibited the preventive effect of GLP-1 on ethanol-induced gastric mucosal damage. GLP-1 also prevented the decrease in gastric mucosal blood flow caused by ethanol when administered at gastroprotective doses (1000 and 10,000 ng/kg; i.p.). In conclusion, GLP-1 administered peripherally prevents the gastric mucosal damage caused by ethanol in rats. CGRP, NO, prostaglandin and gastric mucosal blood flow are thought to play a role in this effect, mediated through receptors specific to GLP-1.

Effect of peripherally-injected glucagon-like peptide-1 on gastric mucosal blood flow.

The aim of this study was to investigate the mechanisms involved in the effect of glucagon-like peptide-1 (GLP-1) on the decrease in gastric mucosal blood flow (GMBF) induced by intragastric ethanol. After preparation of the stomach for GMBF recording, a probe was placed to the gastric mucosa and basal GMBF recordings were obtained by a laser Doppler flowmeter after a 30-minute stabilization period. Following GLP-1 (1000 ng/kg; i.p.) injection, 1 ml of absolute ethanol was applied to the gastric chamber and GMBF was recorded continuously during a 30-minute period. GLP-1 (1000 ng/kg; i.p.) prevented the decrease in GMBF induced by ethanol. Nitric oxide (NO) synthase inhibitor L-NAME, (30 mg/kg; s.c.), calcitonine gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) (10 microg/kg; i.p.), and cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.) all inhibited the GMBF-improving effect of GLP-1. We concluded that, NO, CGRP and prostaglandins may be involved in the effect of peripherally-injected GLP-1 on GMBF reduction induced by intraluminal ethanol.

Arginine vasopressin in the pathogenesis of febrile convulsion and temporal lobe epilepsy

We aimed to investigate the possible convulsant action of arginine vasopressin (AVP) in both a febrile convulsion model in rat pups and a temporal lobe epilepsy model in adult rats and to define the receptor type which mediates this effect. In rat pups, 125 ng V2 receptor antagonist significantly prevented hyperthermic seizures, but did not affect seizure latency. In adult rats, the only effective dose and agent was 125 ng V2 receptor antagonist, which prevented pilocarpine-induced status epilepticus, extended the status epilepticus latency and improved the 24 h survival rate. These data suggest that AVP has a convulsant activity in febrile convulsions and also in seizures independent of fever, and this effect is mediated by V2 receptors.