Anti-inflammatory and antinociceptive activities of glucagon-like peptides: evaluation of their actions on serotonergic, nitrergic, and opioidergic systems.

RATIONALE: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are gut derived hormones. GLP-1 and GLP-2 were shown to have pleiotropic effects in intestinal and pancreatic diseases. OBJECTIVE: We aimed to investigate the activities of GLP-1 and GLP-2 on nociception and inflammation in mice, involving their actions on serotonergic, nitrergic, and opioidergic systems. METHODS: Antinociceptive and anti-inflammatory activities of intraperitoneally injected GLPs were evaluated in hotplate latency test, formalin-induced behavioral, and paw edema tests. Ondansetron, a selective 5-HT3 receptor antagonist; L-NAME, a NOS inhibitor; and naloxone, an opioid antagonist were injected to determine the mechanisms of antinociception and anti-inflammation. We also measured blood glucose levels and performed rotarod test in order to evaluate whether the hypoglycemic effect of GLP compounds or alterations in locomotor activity may affect the latency in hotplate test and activity in formalin test. RESULTS: GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.2 mg/kg) significantly increased pain threshold. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.1, 0.2 mg/kg) significantly decreased formalin-induced licking and shaking behaviors. GLP-1 or GLP-2 showed no significant inhibitory action on formalin-induced swelling in paws of mice. Antinociceptive actions of GLP-1 and GLP-2 were significantly decreased with ondansetron and naloxone, and paw shaking behavior significantly increased with naloxone. GLP-1 and GLP-2 did not impair rotarod performance, and did not cause a significant hypoglycemic effect in our normoglycemic mice after rotarod test. CONCLUSION: These finding indicated that the antinociceptive and anti-inflammatory effect of GLP-1 was related to opioidergic system. Antinociceptive effect of GLP-2 was partially related to 5-HT3 serotonergic or opioidergic system in hotplate test. However, the anti-inflammatory effect of GLP-2 was not directly related to 5-HT3, NO or opioids.

Acute alterations in biochemistry, morphology and contractility of rat isolated urinary bladder via increased intra-abdominal pressure.

OBJECTIVE: To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology and contractility of the rat isolated urinary bladder using an experimental laparoscopy model. METHODS: We divided 24 adult female Sprague-Dawley rats into three groups. The control group (group I) was not subjected to increased IAP. In groups II and III, IAPs of 10 and 20 mm Hg, respectively, were established by carbon dioxide pneumoperitoneum for 60 min. Thirty minutes after desufflation, the rat urinary bladder dome was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) levels and histopathological examination. Statistical comparisons between groups were performed. RESULTS: Tissue MDA levels in groups II and III were significantly higher than in the control group. In group II, only the lamina propria was significantly damaged. However, the epithelium, lamina propria, and serosa were significantly damaged in group III. Acetylcholine potentiated contractions in both IAP groups. Increased responses to electrical field stimulation in the IAP groups were significant only in group II. CONCLUSIONS: In this experimental model, 10 and 20 mm Hg of IAP induced by pneumoperitoneum increased MDA levels and caused important changes in the morphology and contractile response of the urinary bladder.

The acute alterations in biochemistry, morphology, and contractility of rat-isolated terminal ileum via increased intra-abdominal pressure.

AIM AND SCOPE: To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology, and contractility of the isolated terminal ileum of rats. BACKGROUND: Laparoscopic procedures are used clinically in diagnostic and treatment modalities and experimentally as a model of ischemia-reperfusion injury induced by the elevation of IAP. Although some clinical and in vivo experimental studies investigate the results of ischemia-reperfusion injury whether induced by elevated IAP or clamping, there is no in vitro study that has investigated the acute effects of high IAP mimicked by a laparoscopic intervention in any of the intra-abdominal organs (like terminal ileum) on the basis of contractility which represents the motility. METHODS: Twenty-four adult with either sex Sprague-Dawley rats were divided into three groups. The control group (Group I) was not subjected to any IAP. In Groups II and III, an IAP of 10 and 20 mmHg, respectively, was established by carbon dioxide pneumoperitoneum for a period of 60 min. Thirty minutes after the desufflation, the terminal ileum was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) values, and histopathological examination. Statistical comparisons among groups were done using the Kruskal-Wallis variance analysis, with post hoc comparison performed with the Mann-Whitney U-test. RESULTS: Tissue MDA value and the damage scores of mucosa and submucosa were significantly increased in both IAP groups. The smooth muscle layer was significantly damaged only in Group III. The contractions obtained by electrical field stimulation (EFS) were inhibited in both IAP groups, and the contractions to acetylcholine were inhibited in Group III when compared to the control group. CONCLUSIONS: In conclusion, we can say that pneumoperitoneum induced IAP may inhibit contractile responses, cause structural alterations which may be related to ischemia-reperfusion injury in rat terminal ileum.

The contracting and relaxing responses of human internal mammary artery grafts harvested by two different methods.

Perioperative spasm of internal mammary artery is a common experience in coronary artery bypass grafting. Many techniques were described of harvesting the internal mammary artery to prevent vasospasm. We investigated the comparison of the contracting and relaxing responses of human internal mammary artery grafts harvested by two different methods. Patients were divided into two groups depending on the harvesting technique. In the first and second groups arteries were harvested by classical and carbon dioxide insufflation techniques, respectively. In both groups, endothelial function of arteries was assessed by precontracting the rings with phenylephrine (10(-5)M) and dilatating them by cumulative acetylcholine (10(-8) to 10(-5)M) concentrations. Cumulative concentration-response curves for phenylephrine (10(-8) to 10(-4)M), noradrenaline (10(-9) to 10(-4)M), and 5-hydroxytryptamine (10(-9) to 10(-4)M) were obtained in all groups. Endothelial integrity of arteries were histopathologically evaluated. In both groups, acetylcholine caused concentration-dependent relaxations in rings precontracted with phenylephrine (10(-5)M). In arteries harvested by carbon dioxide insufflation technique, acetylcholine caused significantly higher relaxations compared to the rings obtained by classical technique (p<0.05). In all rings of study groups, phenylephrine, noradrenaline and 5-hydroxytryptamine caused concentration-dependent contractions. There was not any significant difference in concentration-dependent responses of these contracting pharmacological agents between the groups. Histopathological evaluation revealed no major arterial damage in both groups. Carbon dioxide insufflation technique does seem not only to protect the integrity of the endothelium and the whole vessel, but also prevent the possible vasospasm of the internal mammary artery segments.

Use of polypharmacotherapy in pregnancy: a prospective outcome in a case.

PURPOSE: Little is known about the risks associated with prenatal exposure to atypical antipsychotics. Our objective is to present a case of exposure to risperidone and quetiapine in pregnancy, and additionally to some other drugs. CASE: Our case (36-year old) has suffered schizophrenia (DSM-IV) for 5 years and used these drugs (risperidone, quetiapine, mirtazapine, thioridazine, diazepam, hydroxyzine, clomipramine, fluvoxamine, alprazolam, carbamazepine, biperiden, haloperidol, ampicillin+sulbactam, enoxaparin, oxerutine) in her third pregnancy. Because of her psychotic condition, Mrs. N.B. was not aware of her pregnancy until 22nd week and the pregnancy could not be terminated. She had a female infant (3000 g, 50 cm) with APGAR scores of 8-9 at the first and fifth minutes at 37th week with an uncomplicated vaginal delivery. The baby was normal. CONCLUSION: This case may contribute to the existing knowledge regarding use of atypical antipsychotics in pregnancy.

Paroxetine alters KCl- or ATP-induced contractile responses of isolated vas deferens in rats chronically treated with ethanol.

Chronic ethanol administration affects many organ systems, including sexual organs. One of these organs is the vas deferens whose contractility can also be altered by selective serotonin re-uptake inhibitors (SSRIs). The aim of the present study, is to evaluate whether paroxetine (PX), a SSRI, can modify the contractile responses of isolated vas deferens obtained from rats chronically treated with ethanol to the contractile agents, potassium chloride (KCl) and adenosine triphosphate (ATP). For 21 days, alcohol was applied with a modified liquid diet to sexually mature male Sprague-Dawley rats (200-240 g). The vas deferens of the rats were excised at the end of day 21 and suspended in the organ baths by classical pharmacological methods. The responses to contractile agents tested were decreased by chronic ethanol treatment in all groups compared to their untreated matches. PX (10(-7) and 10(-6)M) potentiated the contractions to KCl (20-180 mM) and ATP (10(-6) to 10(-3)M) in epididymal portion but its higher concentrations (10(-5) and 10(-4)M) inhibited the responses, both in the control and chronically ethanol treated rat groups. Prazosin (PR), an alpha adrenergic receptor blocker, could not inhibit PX-induced potentiation in lower concentrations of KCl but could inhibit the potentiation occurred at higher concentrations of KCl in epididymal portion both in the control and chronically ethanol treated rat groups. PR also inhibited PX-induced potentiation on the responses to ATP in epididymal portion both in the control and chronically ethanol treated rat groups. In conclusion, all the results obtained in this study, suggest that chronic ethanol treatment decreased the contractility of vas deferens but did not alter the action pattern of PX on responses to KCl and ATP in rat vas deferens. On the other hand, the potentiation of responses to contractile agents induced by PX can be partially considered as the result of inhibition of noradrenaline re-uptake.

The effects of paroxetine on rat isolated vas deferens.

The aim of the present study is to evaluate whether paroxetine (a selective serotonin re-uptake inhibitor) can modify the contractile responses of isolated vas deferens. Some contractile agents, potassium chloride (KCl), adenosine 5'-triphosphate (ATP), noradrenaline (NA), and electrical field stimulation (EFS) caused contractions both in epididymal and prostatic portions of vas deferens. Paroxetine (PX) in concentrations 10(-7) and 10(-6)M potentiated the contractions to KCl and ATP only in epididymal portion but in higher concentrations (10(-5) and 10(-4)M) inhibited the responses in both portions. NA responses were inhibited by PX in all concentrations used, both in prostatic and epididymal portions. Prazosin (PR), an alpha adrenergic receptor blocking agent, inhibited PX-induced potentiation observed for higher concentrations of KCl. PR also inhibited PX-induced potentiation on the responses to ATP in epididymal portion. Pretreatment with PX (10(-7) to 10(-6)M) increased the contractions to EFS but in 10(-5) and 10(-4)M concentrations inhibited them. Even though the preparations were washed out, the inhibited responses of contractile agents could not be restored. After a washout period for PX, when Bay K 8644 (calcium channel activator) was added to the bath medium, the contractile responses to KCl were partially restored. In calcium-free medium, KCl caused contractions in concentrations higher than 80 mM with lower amplitudes which were not affected by PX. Reserpinization did not change the inhibitory pattern of PX's effect on exogenously applied NA in all concentrations tested. In reserpinized rats, the potentiation caused by PX in exogenously applied ATP responses was not observed. In conclusion, we can say that PX has two different effects: inhibition and potentiation of contractions to various agonists. The inhibitory effect of the drug can be explained by a calcium channel blocking activity. The potentiating effect of the drug is mainly related to its presynaptic action, such as NA re-uptake inhibitory effect.