Effects and selectivity of CL 316243, beta-3-adrenoceptor agonist, in term-pregnant rat myometrium.

BACKGROUND/AIMS: Recent evidence supports a predominant role of ß(3)-adrenoceptors at the end of pregnancy in myometrium. This study was designed to characterize the pharmacology of the selective ß(3)-adrenoceptor agonist CL 316243 on oxytocin-induced myometrial contractions and the levels of cAMP and cGMP of myometrial strips isolated from term-pregnant rats. METHODS: Myometrial strips were obtained from term-pregnant Wistar albino rats (n = 10), mounted in organ baths and tested for changes in isometric tension in response to CL 316243 (10(-10)-10(-5) M) on oxytocin-induced myometrial contractions. Effects of CL 316243 on cAMP and cGMP levels in isolated myometrial strips (n = 8) were evaluated by radioimmunoassay kits. We evaluated the effect of increasing concentrations of CL 316243 on myometrial contractions and on contractions of myometrial smooth muscle pretreated with metoprolol, ICI 118.551 and SR 59230A (ß(1)-, ß(2)-, ß(3)-adrenoceptor antagonists, respectively, 10(-6) M). RESULTS: The inhibition of the amplitude of oxytocin-induced contractions by CL 316243 were antagonized with SR 59230A (10(-6) M), but they were not changed by metoprolol (10(-6) M) or ICI 118.551 (10(-6) M). CL 316243 increased cAMP levels compared to the control group. CL 316243 increased cGMP levels, in the CL 316243 group more than in the control group, but this increase is less significant than cAMP levels. CONCLUSION: These results demonstrate that the inhibition of rat myometrial contractions with CL 316243 is mediated by ß(3)-adrenoceptor subtype and increased cAMP and cGMP levels.

Effects of cannabinoid agonists on sheep sphincter of oddi in vitro.

BACKGROUND/AIMS: According to recent studies, the endocannabinoid system plays an important role in both physiological and pathophysiological situations. The purpose of the present study was to investigate the effects of cannabinoid (CB) agonists on isolated sheep sphincter of Oddi (SO)in vitro. METHODS: The isolated sheep SO tissues were mounted in organ baths and tested for isometric tension and cyclic GMP levels (cGMP) in response to the non-selective CB receptor agonist WIN 55,212-2 and the potent CB1 receptor agonist methanandamide in the presence and absence of the selective CB1 antagonist SR 141716A, the selective CB2 antagonist SR 144528 and the nonspecific inhibitor of nitric oxide (NO) synthase L-NAME. RESULTS: CB agonists relaxed SO in a concentration-dependent manner. These relaxations did not reduce in the presence of SR 144528 but were significantly reduced by SR 141716A and L-NAME. Carbachol significantly increased the cGMP levels compared with the control group and both of the CB receptor agonists significantly increased the cGMP levels compared with the control and carbachol groups. On the other hand, L-NAME prevented the increase in cGMP levels caused by CB agonists. CONCLUSION: These results show that the relaxation by the agonists may be through CB1 receptors. The decrease of CB relaxation responses by L-NAME, a nonspecific inhibitor of NO synthase, and the increase of cGMP levels in the SO tissues by CB agonists which decreased by L-NAME show that the relaxation effects of these agonists may also partially be via increasing the NO synthesis or release.

Alterations in spontaneous contractions of rat ileum and jejunum after peritonitis.

The aim of this study was to investigate the effects of peritonitis on spontaneous contractions of ileum and jejunum smooth muscles isolated from rats. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another group of 8 rats underwent a sham operation and acted as controls. Twenty-four hours after the operation, the rats were killed, and their ileum and jejunum smooth muscles were excised and placed in circular muscle direction in a 10 ml organ bath. Changes in the amplitude and frequency of spontaneous contractions were analyzed before and after the addition of different antagonists. Peritonitis induced the decrease in the amplitude and frequency of spontaneous contractions in ileum and jejunum smooth muscles. In control groups, both ileum and jejunum, the amplitude and frequency of spontaneous contractions were significantly elevated in the presence of N(G)-nitro-L-arginine (L-NNA) and indomethacin. In peritonitis groups, both ileum and jejunum, the amplitude and frequency of spontaneous contractions were significantly enhanced in the presence of L-NNA, aminoguanidine, indomethacin and celecoxib compared to control values. In conclusion, peritonitis induces the decrease in the amplitude and frequency of spontaneous contractions of ileum and jejunum that can be attributed to the rise of nitric oxide synthase and cyclooxygenase isoforms levels.

Investigation of acute effects of aflatoxin on rat proximal and distal colon spontaneous contractions.

Aflatoxins are one of the most potent toxic, mutagenic, teratogenic, cancerogenic, and immunosuppresive substances that naturally occurring contaminants of food. There are some studies in various animal species that have reported aflatoxin effects on gastrointestinal systems, but acute effects of aflatoxins have not been clearly investigated. In this study, we aimed to investigate the acute gastrointestinal effects of total aflatoxin on rat isolated proximal and distal colon. Aflatoxin was given cumulatively at 10(-8)-10(-5)M concentrations and the amplitude and frequency of proximal and distal colon contractions were increased significantly. In the presence of atropine sulfate (23.6 nM) and morphine (0.3 microM) the amplitude and frequency of aflatoxin induced spontan contractions in the proximal and distal colon decreased significantly, on the other hand, L-NNA (0.3 microM) increased contractions' amplitude and frequency significantly in the proximal colon but not in the distal colon. In conclusion, aflatoxin may increase the amplitude and frequency of contractions by increasing muscarinic activity or by decreasing NO synthase and/or release in proximal colon and by increasing muscarinic activity in the distal colon. These findings of aflatoxin on isolated rat proximal and distal colon may explain their acute gastrointestinal effects in humans and animals.

Changes in spontaneous contractions of rat ileum by aflatoxin in vitro.

Aflatoxins are a group of mycotoxins produced by toxigenic strains of Aspergillusflavus, Aspergillusparasiticus and Aspergillusnomius as secondary metabolites. Most of the studies on the aflatoxins have focused mainly on their chronic toxic effects but aflatoxins have also a lot of acute effects on the respiratory, cardiovascular and gastrointestinal systems. In this study the acute gastrointestinal effects of the aflatoxins on rat isolated ileum and the possible mechanisms underlying contractile responses to them were investigated. Aflatoxin increased both of the amplitude and the frequency of spontaneous contractions in a dose-dependent manner. Pretreatment with a cholinergic system inhibitor, atropine sulfate (23.6nM), a specific sodium-channel blocker, tetrodotoxin (0.3microM) and an inhibitor of ACh release from terminal motor neurons, morphine (0.3microM) decreased both of aflatoxin induced spontaneous contractions' amplitude and frequency, in contrast a nicotinic ganglionic blocker, hexamethonium chloride (55microM) did not change the aflatoxin effect. But the decrease of amplitude was more than the frequency in the presence of these antagonists. In conclusion, these findings of aflatoxin on isolated rat ileum may explain their acute gastrointestinal effects in humans and animals.

Mechanism of relaxation induced by nicotine in normal and ovalbumin-sensitized guinea-pig trachea.

Nicotine is an irritant molecule in the cigarette that contributes airway hyper-reactivity. The aim of this study was to investigate the mechanism of these effects and effects of nicotine on the isolated trachea preparations from control and ovalbumin-sensitized guinea-pigs. Nicotine (3x10(-5) to 3x10(-4) M) produced concentration-dependent relaxation on isolated trachea preparations precontracted by carbachol (10(-6) M) in both groups. We found that the relaxant effect of nicotine decreased in the presence of N(w)-nitro L-arginine methyl ester (L-NAME) (10(-6) M), and hexamethonium (10(-2) M) but not in the presence of alpha-bungarotoxin (10(-3) M), and tetrodotoxin (3.1x10(-6) M) in isolated trachea preparations in both groups. The relaxant effect of nicotine was less significant in isolated trachea preparations from ovalbumin-sensitized guinea-pigs than from control guinea-pigs (P<0.05). The contractions elicited by carbachol (10(-6) M) were not significantly different in the ovalbumin-sensitized group than in the control group. Nicotine (10(-4) M) significantly increased the cGMP levels in trachea preparations compared with the control preparations.(P<0.05). These results suggest that nicotine-induced relaxation response in normal and ovalbumin sensitized guinea-pigs trachea is at least in part mediated by nitric oxide (NO) since it was significantly reduced in the presence of L-NAME. The decreased relaxation response to nicotine in ovalbumin sensitized guinea-pigs trachea may be due to impaired production and/or liberation of NO.

Additive interaction of intraperitoneal dexmedetomidine and topical nimesulide, celecoxib, and DFU for antinociception.

Nimesulide, celecoxib, and DFU (5, 5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone) are nonsteroidal anti-inflammatory drugs (NSAIDs) with selective cyclo-oxygenase (COX)-2 blocking properties and have potent analgesic and anti-inflammatory activities in oral and parenteral administrations. Dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, is an extremely potent antinociceptive agent. The present study was conducted to evaluate the antinociception induced by nimesulide, celecoxib, and DFU when topically applied on the tail in the absence or presence of intraperitoneal dexmedetomidine. Antinociception was measured in the radiant tail-flick test after immersion of the tail of rat into a solution of dimethyl sulfoxide (DMSO) containing nimesulide, celecoxib, or DFU. Antinociceptive effect of all drugs peaked at 60 min and decreased gradually to baseline levels at 240 min. Nimesulide had a potency lower than those of celecoxib, and DFU. The antinociceptive effect of dexmedetomidine was blocked by systemic pretreatment of selective alpha(2)-adrenoceptor antagonist, atipamezole. This suggests that antinociceptive effects of dexmedetomidine involve alpha(2)-adrenoceptors. Combination of topical COX-2 inhibitors with intraperitoneal dexmedetomidine yielded additive analgesic effect. These results demonstrate an additive interaction between topical COX-2 inhibitors with intraperitoneal dexmedetomidine. These observations are significant for physicians to combine selective COX-2 inhibitors and dexmedetomidine in the management of pain.

Effects of formoterol and BRL 37344 on human umbilical arteries in vitro in normotensive and pre-eclamptic pregnancy.

Alterations in vascular responses to beta-adrenoceptor agonists in normotensive pregnancy and pre-eclampsia are not fully understood. Thus, we studied changes in vasodilator responses to beta(2)-adrenoceptor agonist formoterol and beta(3)-adrenoceptor agonist BRL 37344 on umbilical arteries isolated from normotensive (n=12) and pre-eclamptic (n=12) pregnant women. Changes in the relaxant effect of formoterol and BRL 37344 were investigated by measuring isometric tensions in endothelium-denuded strips of umbilical arteries in the presence or absence of metoprolol, ICI 118.551 and SR 59230A (beta(1), beta(2), beta(3)-adrenoceptor antagonists, respectively, 10(-6) mol/L). Effects of formoterol and BRL 37344 on cAMP levels of umbilical arteries were evaluated by radioimmunoassay kits. Formoterol (10(-10)-10(-4) mol/L) and BRL 37344 (10(-10)-10(-4) mol/L) caused concentration-dependent relaxation of the contraction induced by phenylephrine (10(-5) mol/L) in umbilical artery strips isolated from both groups. E(max) values of formoterol and BRL 37344 (for normotensive pregnant women: 87.33+/-0.87 and 53.25+/-1.17 vs. for pre-eclampsia: 73.68+/-1.58 and 43.64+/-1.19, n=12, P>0.05, respectively) were significantly smaller in strips from pre-eclamptic women (P<0.05), with no significant change in pD(2) values. E(max) values of formoterol were significantly higher than those of BRL 37344 in both tissue (P<0.05). ICI 118.551 and SR 59230A, but not metoprolol, antagonized the relaxant effects of formoterol and of BRL 37344 on umbilical artery strips isolated from normotensive and pre-eclamptic pregnant women. Formoterol and BRL 37344 increased cAMP levels in both groups, but less significant in pre-eclamptic strips (P<0.05). These results suggest that the relaxation caused in human umbilical arteries by formoterol and BRL 37344 is mediated by a mixed population of beta(2)- and beta(3)-adrenoceptor subtypes, with contribution of cAMP. Umbilical arteries from subjects with pre-eclampsia showed a weaker beta(2)- and beta(3)-receptor-mediated relaxation to formoterol and BRL 37344, suggesting that the reduced action of formoterol and BRL 37344 may be partly due to a decreased effect of cAMP.

Comparison of effects of formoterol and BRL 37344 on isolated term-pregnant rat myometrial strips in vitro.

This study was designed to compare the effects of beta-adrenoceptor agonists formoterol and BRL 37344 on spontaneous contractions and the levels of cAMP and cGMP of myometrial strips isolated from timed-pregnant rats. Myometrial strips were obtained from term-pregnant Wistar albino rats (n=12), mounted in organ baths and tested for changes in isometric tension in response to formoterol and BRL 37344. We evaluated the effect of increasing concentrations of formoterol and BRL 37344 on oxytocin-induced myometrial contractions and on contractions of myometrial smooth muscle pretreated with metoprolol, ICI 118.551 and SR 59230A (beta1, beta2, beta3-adrenoceptor antagonist, respectively, 10(-6) M). Effects of formoterol and BRL 37344 on cAMP and cGMP levels in isolated myometrial strips (n=6) were evaluated by radioimmunoassay kits. Formoterol (10(-12)-10(-8) M) and BRL 37344 (10(-11)-10(-5) M) concentration-dependently decreased the amplitude of oxytocin-induced contractions. E(max) value (100%) of formoterol was increased significantly more than E(max) value (70.6%) of BRL 37344 (P<0.05), with no change in pD(2) value (9.54+/-0.12 and 9.12+/-0.12, respectively). The inhibition of the amplitude of oxytocin-induced contractions by formoterol was antagonized with ICI 118.551 (10(-6) M), but they were not changed by metoprolol (10(-6) M) or SR 59230A (10(-6) M). The inhibition of the amplitude of oxytocin-induced contractions by BRL 37344 were antagonized with SR 59230A (10(-6) M), but they were not changed by metoprolol (10(-6) M) or ICI 118.551 (10(-6) M). Formoterol and BRL 37344 increased cAMP levels. BRL 37344 increased cGMP levels in BRL 37344 group more than control group, but this increase is less significant than cAMP levels (P>0.05). Formoterol and BRL 37344 decreased amplitude of myometrial contractions with similar potency, but efficacy of formoterol was better than BRL 37344.

Relaxant effects of beta-adrenoceptor agonist formoterol and BRL 37344 on bovine iris sphincter and ciliary muscle.

We investigated the relaxant effect of beta2-adrenoceptor agonist formoterol and beta3-adrenoceptor agonist BRL 37344 on bovine iris sphincter and ciliary muscle and measured cAMP and cGMP levels. Iris sphincter (n = 16) and ciliary muscle (n = 16) strips were mounted in organ baths and tested for changes in isometric tension in response to formoterol and BRL 37344. Their relaxant effects on serotonin-induced contractions in the presence or absence of metoprolol, ICI 118.551 and SR 59230A (beta1-, beta2-, beta3-adrenoceptor antagonist, respectively) were investigated. Their effects on cAMP and cGMP levels in iris sphincter (n = 12) and ciliary muscle (n = 12) were evaluated. Formoterol (10(-11)-10(-5) M) and BRL 37344 (10(-10)-10(-5) M) decreased the serotonine-induced contractions in a concentration-dependent manner. Emax values of formoterol were significantly higher than those of BRL 37344 in iris sphincter and ciliary muscle, with no significant change in pD2 values. The relaxation responses by formoterol and BRL 37344 were antagonized with ICI 118.551 (10(-6) M) and SR 59230A (10(-6) M). cAMP levels of formoterol- and BRL 37344-treated tissues were significantly higher than those of the control tissues. cGMP levels of BRL 37344-treated tissues were significantly higher than those of control tissues, but this effect of BRL 37344 was less significant than its effect on cAMP levels. beta-adrenoceptor relaxation responses in bovine iris sphincter and ciliary muscle are mediated by a mixed population of beta2- and beta3-adrenoceptor subtypes, with a predominant contribution of cAMP. Potency of formoterol and BRL 37344 was similar, but efficacy of formoterol was better than BRL 37344.

Do antibiotics contribute to postoperative ileus? Contractile responses of ileum smooth muscle in Guinea pigs to long-term parenteral ceftriaxone and ampicillin.

BACKGROUND: Antibiotics may impair small bowel smooth muscle contractility and contribute to postoperative ileus. The aim of this study was to compare the contractile responses of ileum smooth muscle to different agonists in guinea pigs treated with ceftriaxone (Rocephin; F. Hoffman-La Roche, Kaiseraugst, Switzerland) or ampicillin (Ampisina; Mustafa Nevzat Ilaç Sanayii AS, Istanbul, Turkey). METHODS: Twenty-four adult guinea pigs were randomly divided into three groups. Whereas eight of these received ceftriaxone sodium (100 mg/kg per day, i.m.) for 10 days, another eight guinea pigs received ampicillin (50 mg/kg per day, i.m.) for 10 days and the remaining eight served as the control group receiving 1 mL distilled water during 10 days as placebo. By the end of 10 days, the animals were killed and their ilea were excised. Ileum segments were placed in an organ bath; concentration-response relationship for carbachol and histamine were obtained by adding the reagent cumulatively to the bath. RESULTS: pD(2) values being the same, maximum contractile responses (E(max)) to carbachol and histamine were significantly reduced in the ceftriaxone sodium group compared with the control group. No significant differences in E(max) and pD(2) values to carbachol and histamine were observed between the ampicillin group and the control group. CONCLUSION: These data indicate that whereas ceftriaxone may impair small bowel smooth muscle contractility, ampicillin does not. There are implications for the long-term use of parenteral antibiotics in the postoperative period.

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells.

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

Comparative relaxant effects of YC-1 and DETA/NO on spontaneous contractions and the levels of cGMP of isolated pregnant rat myometrium.

This study was designed to compare the effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase activator, and diethylenetriamine-NONOate (DETA/NO), a NO donor, on spontaneous contractions and the levels of cyclic GMP (cGMP) of myometrial strips isolated from timed-pregnant rats. Myometrial strips were obtained from timed-pregnant Wistar albino rats (n=10) and were mounted in organ baths and tested for changes in isometric tension in response to YC-1 and DETA/NO. We also evaluated the effect of YC-1 and DETA/NO on the levels of cGMP in myometrial strips obtained from timed-pregnant rat uterine horns (n=20). YC-1 (10(-9)-3x10(-5) M) and DETA/NO (10(-7)-10(-4) M) concentration-dependently decreased the amplitude and frequency of spontaneous contractions of myometrial strips isolated from term-pregnant rats. The inhibitions of the amplitude and frequency of spontaneous contractions by YC-1 and DETA/NO were antagonized with methylene-blue (10(-5) M). Antagonistic effect of methylene-blue (10(-5) M) was more on DETA/NO responses than that of YC-1 (P<0.05). In addition, YC-1-stimulated myometrial strips showed more elevation in myometrial cGMP than that of DETA/NO (P<0.05). We demonstrated that YC-1 and DETA/NO induce relaxations in the amplitude and frequency of spontaneous contractions of myometrial strips with different potencies. We also found that YC-1 and DETA/NO-induced relaxations are associated with significant increases in cGMP. These results might suggest that the relaxant effects of YC-1 and DETA/NO on the rat myometrium could be due to the stimulation of the soluble guanylate cyclase and cGMP may play a role for the maintenance of uterine quiescence during pregnancy.

Evaluation of effects of T and N type calcium channel blockers on the electroencephalogram recordings in Wistar Albino Glaxo/Rij rats, an absence epilepsy model.

OBJECTIVES: It is suggested that excessive calcium entry into neurons is the main triggering event in the initiation of epileptic discharges. We aimed to investigate the role of T and N type calcium channels in absence epilepsy experimental model. MATERIALS AND METHODS: Wistar Albino Glaxo/Rij (WAG/Rij) rats (12-16 weeks old) were randomly allocated into four groups; sham, mibefradil (T type calcium channel blocker), w-Conotoxin MVIIA (N type calcium channel blocker), and mibefradil + w-Conotoxin MVIIA. Beta, alpha, theta, and delta wave ratios of EEG recordings and frequency and duration of spike wave discharges (SWDs) were analyzed and compared between groups. RESULTS: Beta and delta recording ratios in 1 µM/5 µl mibefradil group was significantly different from basal and other dose-injected groups. Beta, alpha, and theta recordings in 0.2 µM/5 µl w-Conotoxin MVIIA group was significantly different from basal and other dose-injected groups. In w-Conotoxin MVIIA after mibefradil group, beta, alpha, and theta recording ratios were significantly different from basal and mibefradil group. Mibefradil and w-Conotoxin MVIIA significantly decreased the frequency and duration of SWDs. The decrease of frequency and duration of SWDs in mibefradil group was significantly different from w-Conotoxin MVIIA group. The frequency and duration of SWDs significantly decreased in w-Conotoxin MVIIA after mibefradil group compared with basal, mibefradil, and w-Conotoxin MVIIA groups. CONCLUSIONS: We concluded that both T and L type calcium channels play activator roles in SWDs and have positive effects on frequency and duration of these discharges. These results are related with their central effects more than peripheral effects.

Effects of nimesulide and pentoxifylline on decreased contractile responses in rat ileum with peritonitis.

The aim of this study was to determine the effects of nimesulide and pentoxifylline on the contractile effects of KCl, carbachol and substance P in the longitudinal muscle of rat ileum during peritonitis. Peritonitis was induced in rat ileum by cecal ligation and puncture. Thirty rats were operated on to induce peritonitis, 10 of which received nimesulide (5 mg/kg, subcutaneously) and 10 of which received pentoxifylline (25 mg/kg, subcutaneously) before the operation; 10 other rats underwent a sham operation and acted as controls. Twenty-four hours after the operation, ileum segments were transferred to isolated organ baths and responses to KCl, carbachol and substance P were recorded. Emax values of KCl, carbachol and substance P were markedly lower (P<0.05), with no change in the pD2 values, in the peritonitis group than in the controls. Peritonitis-induced changes in the KCl, carbachol and substance P responses of ileum were significantly restored by nimesulide (P<0.05), but not by pentoxifylline. The improved contractile responses following nimesulide treatment indicate that products of cyclooxygenase-II may be, at least in part, responsible for the decreased contractile responses to KCl, carbachol and substance P in peritonitis.

Comparison of effects of cyclooxygenase inhibitors on myometrial contraction and constriction of ductus arteriosus in rats.

The aim of this study was to compare the tocolytic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), indomethacin and nimesulide on myometrial strips isolated from rats in both lipopolysaccharide-induced preterm labour and term labour. We also compared the constrictor effects of DFU and indomethacin on the fetal ductus arteriosus. Myometrial strips were obtained from preterm and term labour Wistar albino rats and were mounted in organ baths for the recording of isometric tension. DFU, nimesulide and indomethacin significantly inhibited KCl-, oxytocin-, prostaglandin E(2)- and prostaglandin F(2 alpha)-stimulated contractions of myometrial strips isolated from rats in preterm and term labour. The E(max) value of indomethacin was significantly lower than those for DFU and nimesulide (P<0.05), with no change-log (10) EC(50) values. There was no significant difference between in -log (10) EC(50) and E(max) values of DFU and nimesulide for any of the tissues (P>0.05). In addition, there was no significant difference between -log (10) EC(50) and E(max) values for each of these three agents in myometrial tissues isolated from rats in preterm and term labour (P>0.05). Fetal ductus arteriosus was significantly constricted by DFU (10 or 100 mg/kg) in preterm and term rats, although DFU (10 or 100 mg/kg)-induced constriction ratios were significantly lower than those for indomethacin (P<0.05). These data demonstrate that DFU, a specific cyclooxygenase-2 inhibitor, could be considered as a new therapeutic agent for preterm labour. However, careful attention should be given to constriction of the fetal ductus arteriosus.

Effects of 5-nitro-2-(3-phenylpropylamino) benzoic acid, anthracene-9-carboxylate, and zaprinast on endothelin-1-induced contractions of pregnant rat myometrium.

OBJECTIVE: The effects of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), anthracene-9-carboxylate (9-AC) (chloride channel blockers) and zaprinast (an inhibitor of phosphodiesterase-5) on endothelin-1 (ET-1) induced contractions of pregnant rat myometrium were investigated in vitro. METHODS: Isolated myometrial strips were obtained from pregnant rats, and the strips were mounted in organ baths for recording of isometric tension (n=8). The effects of 10(-7) to 10(-4)M NPPB, 10(-7) to 10(-4)M 9-AC, and 10(-7) to 10(-4)M zaprinast on 10(-8)M ET-1-induced contractions of pregnant rat myometrial smooth muscle were recorded. RESULTS: NPPB and 9-AC increased the amplitude of ET-1-induced myometrial contractions, while decreasing the frequency, in a concentration-dependent manner. The amplitude of myometrial contractions were significantly increased by NPPB and 9-AC beginning from the concentration of 10(-6)M. The frequency of myometrial contractions were significantly decreased by NPPB and 9-AC beginning from the concentration of 10(-6)M. Zaprinast inhibited the amplitude and frequency of ET-1-induced myometrial contractions in a concentration-dependent manner. Zaprinast-induced decreases in amplitude and frequency of myometrial contractions reached statistical significance beginning from the concentrations of 10(-7)M and 10(-5)M, respectively. CONCLUSION: These data provide evidence that the ET-1-induced contractions of pregnant rat myometrial strips may be modulated by chloride channels. In addition, zaprinast effectively inhibited ET-1-induced contractions in pregnant rat myometrium.

Comparison of the effects of nimesulide and 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU) on contractions of isolated pregnant human myometrium.

OBJECTIVE: To compare the effects of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU) and nimesulide, selective COX-2 inhibitors, on the amplitude and frequency of KCl-, oxytocin-, and PGF(2alpha)-stimulated contractions of isolated pregnant human myometrial strips. METHODS: Isolated myometrial strips were obtained from 20 pregnant women undergoing elective cesarean section. These strips were mounted in organ baths for recording of isometric tension. The effects of cumulative concentrations of nimesulide and DFU on KCl-, oxytocin-, and PGF(2alpha)-stimulated myometrial contractions were measured, and values for -log(10)EC(50) and mean maximal inhibition (E(max)) were compared. Nimesulide (10(-8) to 10(-4)M) and DFU (10(-8) to 10(-4)M) inhibited in a concentration-dependent manner the KCl-, oxytocin-, and PGF(2alpha)-stimulated contractions of myometrial strips, with a significant effect on the amplitude (10(-7) to 10(-4)M) and the frequency (10(-6) to 10(-4)M). RESULTS: The inhibitor effect of DFU was more potent than nimesulide on KCl-, oxytocin-, and PGF(2alpha)-stimulated myometrial contractions, however, the inhibitor effects of nimesulide and DFU was much greater on KCl-stimulated contractions than on oxytocin- and PGF(2alpha)-stimulated myometrial contractions (P < 0.05). There was no significant difference between E(max) values of nimesulide and DFU in all tissues (P > 0.05). CONCLUSION: DFU is a more potent inhibitor than nimesulide on KCl-, oxytocin-, and PGF(2alpha)-stimulated contractions of pregnant human myometrium. The inhibitor effects of nimesulide and DFU were predominantly on KCl-stimulated contractions.

Anticancer effect of COX-2 inhibitor DuP-697 alone and in combination with tyrosine kinase inhibitor (E7080) on colon cancer cell lines.

Colorectal cancer remains one of the most common types of cancer and a leading cause of cancer death worldwide. In this study, we aimed to investigate effects of DuP-697, an irreversible selective inhibitor of COX- 2 on colorectal cancer cells alone and in combination with a promising new multi-targeted kinase inhibitor E7080. The HT29 colorectal cancer cell line was used. Real time cell analysis (xCELLigence system) was conducted to determine effects on colorectal cell proliferation, angiogenesis was assessed with a chorioallantoic membrane model and apoptosis was determined with annexin V staining. We found that DuP-697 alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. For the antiproliferative effect the half maximum inhibition concentration (IC50) was 4.28?10-8 mol/L. Antiangiogenic scores were 1.2, 0.8 and 0.5 for 100, 10 and 1 nmol/L DuP-697 concentrations, respectively. We detected apoptosis in 52% of HT29 colorectal cancer cells after administration of 100 nmol/L DuP-697. Also in combination with the thyrosine kinase inhibitor E7080 strong antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells were observed. This study indicates that DuP-697 may be a promising agent in the treatment of colorectal cancer. Additionally the increased effects observed in the combination with thyrosine kinase inhibitor give the possibility to use lower doses of DuP-697 and E7080 which can avoid and/or minimize side effects.

Effects of proton pump inhibitors and h(2) receptor antagonists on the ileum motility.

Objectives. To investigate the effects of proton pump inhibitors (PPIs) and H(2) receptor antagonists on ileum motility in rats with peritonitis and compare changes with control group rats. Methods. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another of 8 rats underwent a sham operation and were accepted as controls. Twenty-four hours later after the operation, the rats were killed, and their ileum smooth muscle was excised and placed in circular muscle direction in a 10 mL organ bath. Changes in amplitude and frequency of contractions were analyzed before and after PPIs and H(2) receptor blockers. Results. PPI agents decreased the motility in a dose-dependent manner in ileum in both control and intraabdominal sepsis groups. While famotidine had no significant effect on ileum motility, ranitidine and nizatidine enhanced motility in ileum in both control and intraabdominal sepsis groups. This excitatory effect of H(2) receptor antagonists and inhibitor effects of PPIs were significantly high in control group when compared to the peritonitis group. The inhibitor effect of pantoprazole on ileum motility was significantly higher than the other two PPI agents. Conclusions. It was concluded that H(2) receptor antagonists may be more effective than PPIs for recovering the bowel motility in the intraabdominal sepsis situation.