Myrtus communis improves cognitive impairment in renovascular hypertensive rats.

Myrtus communis has anti-inflammatory, neuroprotective and anticholinesterase activities yet there have been limited studies examining effects of Myrtus communis on cognitive functions. This study investigated the possible effects of Myrtus communis on changes in the cognitive functions of experimental renovascular hypertensive rats. Fifty-six Wistar-Albino rats were equally divided into 4 groups; sham-operated control, renovascular hypertension (RVH), ramipril (RVH + Ram) and Myrtus communis extract (RVH + MC) treatment groups. Goldblatt's 2-kidney 1-clip (2K1C) method was used to induce RVH. At the end of 9 weeks of treatment, after blood pressure recording, the animals underwent new object recognition test and Morris water maze (MWM) task. Following these tests, blood brain barrier (BBB) integrity was examined in 6 animals from each group. In the others after decapitation, osteopontin and interleukin (IL)-10 levels were measured in blood samples; while matrix metalloproteinase (MMP)-13, sodium potassium adenosine triphosphatase (Na+,K+-ATPase), cluster of differentiation (CD) 36, amyloid beta (Aß), neprilysin levels, and acetylcholinesterase (AChE) activity were investigated in hippocampal tissues. In RVH group, high systolic blood pressure decreased serum IL-10 levels, increased serum osteopontin levels and also impaired BBB permeability. Hippocampal MMP-13, CD36, Aß, neprilysin levels and AChE activities were elevated, while there were decreases in Na+,K+-ATPase levels. In new objet recognition test, discrimination index (DI) was determined as lower in saline-treated RVH group compared to control animals. In MWM training trail, 4th day performance in finding platform was significantly reduced in saline-treated RVH group compared to control group. RVH also decreased the time spent in target quadrant in probe test of MWM task compared to control group. In both of the treatment groups, all biochemical parameters were restored in parallel with improvement in the behavioral test performances. The results of this study suggest that Myrtus communis extract may improve the cognitive dysfunctions in hypertension through antihypertensive, anti-inflammatory and anticholinesterase activities.

Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers.

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.

Anti-inflammatory effects of nesfatin-1 on acetic acid-induced gastric ulcer in rats: involvement of cyclo-oxygenase pathway.

In order to elucidate the contribution of cycloxygenase (COX) enzymes in the anti-oxidant and anti-inflammatory mechanisms of nesfatin-1, which improves the healing process of chronic gastric ulcers, either acetic acid (80%; ulcer groups; n = 40) or saline (control groups; n = 40) was applied to the serosal surface of male Sprague Dawley rats' stomachs for 1 min. Both the control and ulcer groups were treated daily with either i.p. saline or nesfatin-1 (0.3 µg/kg; for 3 days). Nesfatin-1-treatment was preceded with i.p. saline, COX-2 inhibitor NS-398 (2 mg/kg), COX-1 inhibitor ketorolac (3 mg/kg) or non-selective COX inhibitor indomethacin (5 mg/kg) for 3 days. The rats were decapitated at the end of the third day, and their trunk blood was collected for the measurements of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-10 using ELISA. The induction of ulcers resulted in increased macroscopic scores, along with elevated gastric malondialdehyde, luminol- and lucigenin-enhanced chemiluminescence levels and myeloperoxidase activity. On the other hand, nesfatin-1 treatment abolished these elevations. Depleted glutathione, superoxide dismutase and catalase activity levels in the saline-treated ulcer group were preserved in the nesfatin-1-treated ulcer group. Increased levels of serum TNF-α, IL-1ß, IL-10 in the saline-treated ulcer group, as compared to control group, were significantly decreased in the nesfatin-1-treated ulcer group. The inhibition of COX-1, and/or COX-2 reversed most of the alterations induced with nesfatin-1, but COX-2-blockade was consistently more effective to abolish all nesfatin-1-induced changes. Our results suggest that nesfatin-1 ameliorates ulcer-induced inflammatory response through the modulation of oxidant-antioxidant balance. As selective pharmacological inhibition of COX-1 or COX-2 suppresses the antioxidant/anti-inflammatory effects of nesfatin-1, it appears that nesfatin-1 decreases inflammatory mediators and neutrophil migration by a COX-dependent mechanism, especially by a COX-2- dependent mechanism, during the ulcer healing stage.

Propylthiouracil-induced hypothyroidism protects ionizing radiation-induced multiple organ damage in rats.

The objective of this study was to examine the potential radioprotective properties of propylthiouracil (PTU)-induced hypothyroidism against oxidative organ damage induced by irradiation. Sprague-Dawley rats were pre-treated with saline or PTU (10 mg/kg i.p.) for 15 days, and were then exposed to whole-body irradiation (800 cGy). A group of rats were decapitated at 6 h after exposure to irradiation, while another group was followed for 72 h after irradiation, during which saline or PTU injections were repeated once daily. Lung, liver, kidney and ileum samples were obtained for the determination of malondialdehyde (MDA; an index of lipid peroxidation) and glutathione (GSH, an antioxidant) levels, myeloperoxidase activity (MPO; an index of tissue neutrophil accumulation) and collagen contents, while oxidant-induced DNA fragmentation was evaluated in the ileal tissues. All tissues were also examined microscopically and assayed for the production of reactive oxidants using chemiluminescence (CL). Lactate dehydrogenase (LDH), an indicator of tissue damage, and tumour necrosis factor-alpha (TNFalpha) were assayed in serum samples. Irradiation caused a significant decrease in GSH level, which was accompanied by significant increases in MDA levels, MPO activity, CL levels and collagen content of the tissues studied (P<0.05-0.001). Similarly, serum TNFalpha and LDH were elevated in the irradiated rats as compared with the control group. On the other hand, PTU treatment reversed all these biochemical indices, as well as histopathological alterations induced by irradiation. Our results suggested that PTU-induced hypothyroidism reduces oxidative damage in the lung, hepatic, renal and ileal tissues probably due to hypometabolism, which is associated with decreased production of reactive oxygen metabolites and enhancement of antioxidant mechanisms.

Regular exercise alleviates renovascular hypertension-induced cardiac/endothelial dysfunction and oxidative injury in rats.

The importance of physical activity in the management of renovascular diseases is well-known, but lacks evidence of underlying mechanisms. The purpose of the study was to elucidate the protective/therapeutic effects of regular exercise on experimental renovascular hypertension (RVH)-induced oxidative stress and cardiac dysfunction. Wistar albino rats underwent a RVH surgery (2K1C, Goldblatt). Three weeks later half of the rats started swimming exercise for 9 weeks (n = 15), while the sedentary RVH group (n = 15) had no exercise during that period. Sham-operated control rats (n = 10), had the similar surgical procedures but the left renal artery was left unclipped. Body weights were monitored, and blood pressures were measured weekly using tail-cuff. Echocardiographic evaluation was performed on the 3(rd) week and on the 12(th) week of the experiment before the rats were decapitated. Heart and thoracic aorta were removed and serum was collected, while aortic samples were put in a 10% formaldehyde solution for immunochemistry. Cardiac tissue samples obtained from each animal were used for the determination of tissue myeloperoxidase (MPO) and catalase (CAT) activities, malondialdehyde (MDA), and glutathione (GSH) levels. In the sedentary RVH group, aortic contractile response (contraction/relaxation in isolated organ bath), left ventricular diastolic and systolic dimensions, and immunohistochemical staining of aortic inducible nitric oxide synthase (iNOS) were increased, while ejection fraction and aortic endothelial nitric oxide synthase (eNOS) staining were decreased. RVH in the sedentary rats resulted in increased pro-inflammatory cytokines (TNF-α, IL-2, IL-6), lipid peroxidation (malondialdehyde) and neutrophil infiltration (myeloperoxidase activity) along with reductions in antioxidant glutathione and catalase levels in the cardiac tissue. Exercise after RVH increased the immunohistochemical staining of aortic eNOS, decreased iNOS staining and reversed the alterations in echocardiographic and oxidative parameters. Regular exercise commenced after RVH surgery alleviated renovascular hypertension-induced oxidative injury, by modulating oxidant-antioxidant balance via the involvement of the endothelial NO system.

Ghrelin against alendronate-induced gastric damage in rats.

Alendronate sodium, a primary amino bisphosphonate, is widely used in the treatment of various diseases that are associated with bone resorption, such as postmenopausal osteoporosis and Paget's disease of bone. Although the adverse effects of biphosphonates on the gastrointestinal system have been demonstrated in experimental and clinical studies, the exact mechanisms underlying this damage are not clear yet. Ghrelin, a 28 amino acid peptide produced predominantly by the stomach, was shown to exert a potent protective action on the stomach of rats exposed to ethanol or stress. Our objective was to evaluate the possible anti-oxidant and anti-inflammatory effects of ghrelin against alendronate-induced gastric damage. Wistar albino rats were administered alendronate (20 mg/kg) by gavage for 4 days, along with either ghrelin (10 ng/kg per day) or saline given i.p. After decapitation, stomach tissues were removed for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and tissue collagen content, while the extent of tissue damage was analyzed microscopically. Formation of reactive oxygen species was determined by chemiluminesence using a luminol probe in fresh gastric tissues. Serum tumor necrosis factor (TNF-alpha) and lactate dehydrogenase levels were assessed in trunk blood. Oral administration of alendronate-induced significant gastric damage, accompanied by increased MPO activity, collagen content, MDA and luminol levels (P < 0.01-P < 0.001), while tissue GSH was decreased (P < 0.01). On the other hand, ghrelin treatment reversed these alterations (P < 0.05-P < 0.001) as well as elevating serum TNF-alpha levels significantly (P < 0.001). The findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect, and ghrelin ameliorates this damage by its possible antioxidant and anti-inflammatory properties.

Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors.

Pineal hormone melatonin is proposed as a potential treatment for severe sleep disturbances, and various gastrointestinal disorders. It was shown that melatonin increases intestinal motility and influences the activity of myoelectric complexes of the gut. The aim of the study was to evaluate the mechanisms of the effect of exogenous melatonin on gastric emptying rate. Male Sprague-Dawley rats were fitted with gastric cannulas under anesthesia. The rate of gastric emptying of saline was determined after instillation into the gastric fistula, from the volume and phenol red concentrations recovered after 5 min. Melatonin injected intraperitoneally (ip; 0.001-100 mg/kg) delayed gastric emptying rate of saline at 3 and 10 mg/kg doses. When administered ip 15 min before melatonin (10 mg/kg) injections, CCK2 (L-365,260, 1 mg/kg) or 5-HT3 receptor (ramosetrone, 50 microg/kg) blockers abolished melatonin-induced delay in gastric emptying rate, while the blockade of sympathetic ganglia (bretylium tosylate, 15 mg/kg) significantly reduced the delay in gastric emptying rate. CCK1 receptor blocker (L-364,718, 1 mg/kg) had no significant effect on the delaying action of melatonin. Our results indicate that pharmacological doses of melatonin delay gastric emptying via mechanisms that involve CCK2 and 5-HT3 receptors. Moreover, it appears that exogenous melatonin inhibits gastric motility in part by activating sympathetic neurons.

The physiology of learning and memory: role of peptides and stress.

The neuropeptides, as well as their respective receptors, are widely distributed throughout the mammalian central nervous system. During learning and memory processes, besides structural synaptic remodeling, changes are observed at molecular and metabolic levels with the alterations in neurotransmitter and neuropeptide synthesis and release. While there is consensus that brain cholinergic neurotransmission plays a critical role in the processes related to learning and memory, it is also well known that these functions are influenced by a tremendous number of neuropeptides and non-peptide molecules. Arginine vasopressin (AVP), oxytocin, angiotensin II, insulin, growth factors, serotonin (5-HT), melanin concentrating hormone, histamine, bombesin and gastrin-releasing peptide (GRP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), dopamine, corticotropin releasing factor (CRF) have modulatory effects on learning and memory. Among these peptides CCK, 5-HT and CRF play strategic roles in the modulation of memory processes under stressful conditions. CRF is accepted as the main neuropeptide involved in both physical and emotional stress, with a protective role during stress, possibly through the activation of the hypothalamo-pitiuitary (HPA) axis. The peptide CCK has been proposed to facilitate memory processing and CCK-like immunoreactivity in the hypothalamus was observed upon stress exposure, suggesting that CCK may participate in the central control of stress response and stress-induced memory dysfunction. On the other hand, 5-HT appears to play a role in behaviors that involve a high cognitive demand and stress exposure activates serotonergic systems in a variety of brain regions. The physiological role and therapeutic efficacy of various neuropeptides and the impact of stress exposure in the acquisition and consolidation of memory will be reviewed thoroughly.

Bombesin-like peptides: candidates as diagnostic and therapeutic tools.

Bombesin (BBS) is proved to have a wide variety of the pharmacologic effects, including effects on the release of gastrointestinal hormones and control of gastrointestinal motility. More recently, the role of BBS in tumor growth, cellular proliferation and inflammation has attracted attention. There is evidence that increased BBS receptor expression may be considered as a specific marker for small-cell lung cancer, colorectal adenocarcinoma, gastric and pancreatic cancer, prostate, ovarian and breast cancer, neuroblastoma, renal cell carcinoma, malignant melanoma and thyroid carcinoma. BBS expression was found to be correlated with the histological grade of the tumor. Similarly, BBS treatment significantly improves the healing of chronic gastric ulcers and ameliorates the severity of burn- or colitis-induced gut injury. Although there is much complexity still to be elucidated to understand fully the physiologic and pathologic roles of BBS-like peptides several clinical or experimental trials have addressed that circulating or tissue levels of BBS-like peptides or their receptor expression may be used as diagnostic or prognostic markers of neoplastic disease, and incorporation of BBS receptor antagonists in the treatment of human cancer could provide substantial benefit to the cancer patients. Moreover, trophic, anti-ulcerogenic and anti-inflammatory actions of exogenous BBS make this peptide a potential supplement in minimizing or reversing tissue damage against several injurious challenges. In conclusion, based on the evidence summarized herein, related to the mitogenic and anti-inflammatory effects of BBS-like peptides, further investigations are needed to derive the benefit of BBS-like peptides in pharmacologic strategies.

Cefaclor, a cephalosporin antibiotic, delays gastric emptying rate by a CCK-A receptor-mediated mechanism in the rat.

Studies in vitro suggest that cephalosporin antibiotics release the gut hormone cholecystokinin. Cholecystokinin is known to inhibit gastric emptying. Here we examine the effects of cefaclor on gastric emptying and intestinal motility. Male Sprague-Dawley rats were fitted with gastric cannulas. Following a 3-week recovery, the rate of gastric emptying of saline, peptone (4.5%) or cefaclor was determined after instillation into the gastric cannula, while intestinal transit was measured by using the propagation of arabic gum + charcoal mixture given intraduodenally. Gastric emptying of saline was significantly delayed by the addition of cefaclor (3, 10, 30 or 100 mM). The CCK-A antagonist SR-27897B (1 mg kg(-1), i.p.) reversed the delay induced by 10 mM cefaclor, whereas the CCK-B antagonist CI-988 (1 mg kg(-1), i.p.) had no significant effect. In capsaicin-treated rats, 10 mM cefaclor emptied more rapidly than in vehicle-treated animals. Thirty-minute intestinal transit was increased at 30 and 100 mM of cefaclor, while the gastric acid secretion following cefaclor instillation was no different than the group which received saline. The cephalosporin antibiotic cefaclor appears to be a potent stimulant of CCK release from gut endocrine cells, resembling the effects of peptone. Cefaclor delays gastric emptying via capsaicin-sensitive afferent pathways, which involve CCK-A receptor interaction.

Methimazole-induced hypothyroidism in rats ameliorates oxidative injury in experimental colitis.

Depression of metabolism by hypothyroidism decreases oxidant production and thus protects tIssues against oxidant damage. Moreover, it is well-known that abnormal gut motility is a common manifestation in hypo/hyperthyroidism. In this study, we aimed to investigate the putative beneficial effects of methimazole on oxidative injury and dysmotility in a rat colitis model. Methimazole (0.04%) was administered in drinking water starting 15 days prior to induction of colitis. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid (30 mg/ml; 0.8 ml) in ethanol. Six days after the induction of colitis, the fecal output was measured and used as an index for colonic motility. All rats were decapitated on the seventh day. The distal colon was weighed and the mucosal lesions were scored. Colonic lipid peroxidation (LP) and glutathione (GSH) measurements were performed. The macroscopic score, the colonic wet weight and LP values of the euthyroid colitis group were found to be higher than those of the control group (P<0.05-0.001). All these parameters were reduced in the methimazole-treated colitis group (P<0.01-0.001). The decrease in colonic GSH levels in the colitis group was completely abolished in the methimazole-treated colitis rats (P<0.01). Induction of colitis increased the average fecal output compared with the control group (P<0.05) and methimazole in the colitis group exaggerated the fecal output (P<0.001). In conclusion, methimazole reduces colonic oxidative injury probably due to hypometabolism, which is associated with a decrease in the production of reactive oxygen intermediates and an increase in the response of antioxidant systems.

The effect of hyperthermic preconditioning on the immune system in rat peritonitis.

OBJECTIVE: To assess whether hyperthermic (HT) preconditioning prevents the lethal effects of peritonitis by acting on the immune system. DESIGN: Prospective, controlled, experimental study. SETTING: Laboratory and animal facility of the university. MATERIALS: Adult male Sprague-Dawley rats. INTERVENTIONS: In the HT groups animals were subjected to hyperthermia (42 degrees C, 15 min) and 8 h later peritonitis (P) (n = 14) was induced. In the normothermic (NT) groups, animals were subjected to normothermia (38 degrees C, 15 min) and 8 h later peritonitis (n = 14) was induced. Each group had a corresponding sham laparotomy group (n = 14). Six rats from each group were allowed to live 7 days for survival. In the control group (n = 4), rats were not anesthetized or heat treated. MEASUREMENTS AND RESULTS: Sixteen hours after peritonitis and laparotomy, rats were killed. Blood was taken to measure the percentage of CD(4)(+), CD(8)(+), CD(4)(+)CD(56)(+), CD(8)(+) CD(11 b)(+), NK(+), B cells and the level of tumor necrosis factor. Grading of peritonitis and the measurement of free oxygen radicals in the peritoneal fluid were undertaken. All rats in the HT + P and sham laparotomy groups survived for 7 days, while in the NT + P group two rats died in 7 days. HT decreased the severity of peritonitis and increased the free oxygen radicals in the peritoneal fluid; however, the difference did not reach statistical significance. HT prevented the decrease in CD(4)(+) and B cells and the increase in CD(11 b)(+). CONCLUSIONS: HT may have a protective role in sepsis by reducing the severity of peritonitis. A causal relation between hyperthermia and an improved immune system seems possible.

The protective effect of 5-HT3 receptor antagonist in thyrotropin releasing hormone-induced gastric lesions.

The present study examined 1) oxidative stress and gastric lesions induced by thyrotropin releasing hormone (TRH) 2) The effect of a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, ICS 205930 on protective effect of calcitonin on gastric lesions produced by TRH. Calcitonin (5 micrograms/10 microliter) was injected i.c.v. 10 min before TRH (10 micrograms/10 microliter, i.c.v.) injection or ICS 0.5 mg/kg, (i.p.) was given 60 min prior to calcitonin or TRH to rats. Ulcer index, lipid peroxidation (LP) and glutathione (GSH) levels were quantified 3 h after TRH injection in the stomach, liver and brain. TRH caused mucosal lesions (UI: 10.0 +/- 2.0 mm) without changing gastric GSH and LP. JCS did not alter the protective effect of calcitonin against TRH-induced lesions but attenuated. TRH-induced lesion formation. The oxidative effects of calcitonin or ICS were similar to TRH but both drugs attenuated gastric lesion formation. Hence, oxidative changes in tissues studied are not directly involved in TRH-induced lesions.

Bombesin improves burn-induced intestinal injury in the rat.

This study was designed to determine the effect of exogenous bombesin (10 microg/kg/day, subcutaneously, three times a day) on intestinal hypomotility and neutrophil infiltration in the early and late phases of burn injury (partial-thickness, second-degree burn of the skin). In acute (2 h after burn injury) or chronic (3 days after) burn groups, intestinal transit was delayed, which was reversed by bombesin treatment. In the acute burn group, but not in the chronic group, increased MPO activity was also reduced by bombesin treatment. The results demonstrate that bombesin ameliorates the intestinal inflammation due to burn injury, involving a neutrophil-dependent mechanism.

The effect of alpha-melanocyte stimulating hormone on colonic inflammation in the rat.

The effect of alpha-melanocyte stimulating hormone (alpha-MSH) on colonic inflammation in the rat. In this study, we investigated the effects of alpha-MSH administration on trinitrobenzene sulfonic acid-induced colitis and the role of nitric oxide and prostaglandins in this response. alpha-MSH treatment (25 microg/rat, intraperitoneally; twice daily for 3 days) reduced the colonic macroscopic lesions compared to untreated ones in both acute and chronic colitis groups. This effect was reversed by pretreatment with the nitric oxide donor, sodium NP (4 mg/kg, intravenously) or cyclooxygenase-1 selective antagonist indomethacin (5 mg/kg, subcutaneously) in the acute group and with the cyclooxygenase-2 selective antagonist nimesulide (3 mg/kg, subcutaneously) in the chronic group. alpha-MSH had no effect on colonic wet weight and myeloperoxidase activity compared to the untreated colitis group. However, protein oxidation was markedly elevated in the alpha-MSH-treated group compared to untreated ones. Nitroprusside and indomethacin reversed the effect of alpha-MSH on macroscopic lesions in the acute groups, whereas nimesulide showed a similar effect in the chronic group. In conclusion, the results of our study show a protective role of alpha-MSH on colonic lesions which partially involves nitric oxide and prostaglandins.

Pathways mediating CRF-induced inhibition of gastric emptying in rats.

The corticotrophin-releasing factor (CRF) is shown to be released during stress suggesting that CRF has a physiological role in the mediation of central nervous system (CNS) response to stress, including an inhibitory effect on gastric emptying. In the present study, we have examined the pathways by which intracerebroventricularly (i.c.v.) administered CRF and central CRF activation during stress alter the gastric emptying rate of saline (0.14 M), acid (50 mM), peptone (4.5%) and peptone after preload. The emptying rates of all these test meals were significantly (p < 0.05-0.001) delayed with increasing doses of i.c.v. CRF (0.001, 0.003, 0.01, 0.1, 0.3 and 1 nmol/10 microl), when compared with their i.c.v. saline-treated controls. The 1-nmol dose of CRF inhibited the emptying of acid, peptone and peptone after a preload by 43.8%, 64.1% and 81.1%, respectively. Twenty-minute swim stress delayed gastric emptying rate of saline, acid and peptone solutions significantly (p < 0.001) and the CRF receptor antagonist, alpha-helical CRF (8 nmol/10 microl, i.c.v.), applied before the swim stress, abolished the inhibitory effect of stress on the emptying rate of these solutions. Acute intragastric administration of capsaicin (2 mg/rat) and systemic capsaicin (125 mg kg(-1)) treatment facilitated the gastric emptying rate of acid, peptone and peptone after preload significantly, almost abolishing the inhibitory effect of central CRF (p < 0.001). However, either capsaicin treatment had no effect on stress-induced inhibition of the gastric emptying of none of the solutions, except peptone after a preload. Our findings demonstrate that the gastric inhibitory response induced by swimming as a stress-producing stimulus is mediated by the endogenous release of CRF. They also suggest that CRF exerts its CNS actions on the gastrointestinal tract via vago-vagal, capsaicin-sensitive pathways, probably involving the central cholecystokinin (CCK) mechanisms.

Inhibitory effects of gastrin releasing peptide on gastric emptying in rats.

Gastrin-releasing peptide (GRP) has a wide range of biological actions, including stimulation of the frequency of antral contractions and delaying gastric emptying. The present study was designed to evaluate the role of GRP in the control of gastric emptying of liquid test meals in the rat. The emptying of methyl cellulose given by gavage to fasted rats, or of saline given via the fistula to conscious gastric fistula rats was not influenced by the GRP antagonists, NC-8-89 (Leu13-psi-(CH2NH)-Leu14-bombesin) and 2258U89 ((de-NH2)Phe19, D-Ala24, D-Pro26 psi (CH2NH)Phe27(-GRP (19-27)), at 2 mg/kg, s.c. However, both antagonists (0.02, 0.2 and 2 mg/kg) reversed the inhibitory effect of HCI on gastric emptying in gastric fistula rats (P < 0.05-0.001). When peptone was administered after a preload, but not otherwise, the inhibition of emptying was also partly reversed by both antagonists at all doses used (P < 0.05-0.001). Interestingly, the delay in the emptying of hyperosmolal saline compared to saline, was enhanced at a dose of 0.2 mg/kg of both antagonists (P < 0.05 and P < 0.01). Food intake did not change significantly with the two lower doses of antagonists, but was decreased by the highest dose of NC 8-89. We conclude that GRP specifically inhibits gastric emptying of acid and peptone solutions in the conscious rat.

Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.

Prostaglandin E2 and leukotriene C4 levels following different reperfusion periods in rat brain correlated with morphological changes.

Prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) are the metabolites of arachidonic acid (AA) that increase in forebrain following global ischemia and reperfusion. These mediators are highly potent vasoconstrictors of cerebral arteries leading to enhanced vascular permeability that induces the formation of vasogenic edema. In this study, after developing an experimental animal model simulating the concept of ischemic penumbra in the rat, the levels of PGE2 and LTC4 produced in the forebrain were measured and the effects of these mediators in short duration and prolonged reperfusion were investigated and then correlated with neuropathological findings. We found statistically significant reduction both in PGE2 and LTC4-like activities after just 10 min ischemia (p less than 0.05, p less than 0.05). PGE2-like activity significantly increased in the 4th and 60th min of reperfusion (p less than 0.05, p less than 0.05). In the 15th min of reperfusion, PGE2 was found to be significantly reduced (p less than 0.005) that may be due to the formation of free oxygen radicals by activation of PG hydroperoxidase reaction that inhibits PGE2 production in the cyclooxygenase pathway. LTs were not significantly increased in any reperfused group. Inhibition of the lipoxygenase pathway of AA metabolism may occur as a result of 15-HPETE (15-hydroperoxyeicosatetraenoic acid) production. Pathologically, edema and degeneration of brain tissue were seen beginning from the 4th min of reperfusion that reached a peak in the 60th min of reperfusion which is in accordance with biochemical changes in the damaged tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of nordihydroguaiaretic acid on leukotriene C4 and prostaglandin E2 production following different reperfusion periods in rat brain after forebrain ischemia correlated with morphological changes.

Leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) are the 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acid (AA). They constrict blood vessels and enhance vascular permeability inducing vasogenic edema that may hurt the ischemic penumbra after cerebral ischemia and reperfusion. Nordihydroguaiaretic acid (NDGA) is known as the most potent inhibitor of 5-lipoxygenase in different tissues. Furthermore, it has considerable inhibitory activity against cyclooxygenase. In this study, after developing a global ischemic model in the rat, the levels of LTC4 and PGE2 in the forebrain were measured, following different reperfusion periods after 10 min ischemia including 8 rats for each reperfused group. Sham operations were performed for each corresponding control group (n = 8). AA metabolites were then correlated with neuropathological findings. In the combined reperfused groups both metabolites increased significantly when compared with 10 min, ischemic group (P < 0.05). In the 8 min reperfused group, PGE2 and LTC4 increased significantly compared with each corresponding control group (P < 0.005). These mediators also increased to high levels compared with the 4 min reperfused group (P < 0.05, P < 0.005). PGE2 and LTC4 were reduced significantly at the 15th and 60th min of reperfusion compared with the 8 min reperfused group (P < 0.05, P < 0.005). NDGA (0.1 mg/kg) reduced both metabolites in the 8 min reperfused group significantly (P < 0.05). Brain cortex specimens were taken for light and electromicroscopical investigations. No significant differences were noted between the structural changes in the 4, 8 and 15 min of reperfusion and NDGA administered groups.(ABSTRACT TRUNCATED AT 250 WORDS)