Gastric effects of the selective cyclooxygenase-2 inhibitor, celecoxib, in the rat.

BACKGROUND: Recent studies have revealed that cyclooxygenase-2 is involved in the protection of the damaged gastric mucosa, mediating, in particular, the acceleration of ulcer healing and angiogenesis; therein, it has been suggested that selective cyclooxygenase-2 inhibitors, although safe in healthy stomach, may have deleterious effects on the injured gastric mucosa. Moreover, no information is available about direct effects of these drugs on gastric surface epithelium. AIMS: To investigate the gastric effects of the selective cyclooxygenase-2 inhibitor, celecoxib, in healthy and damaged rat gastric mucosa. METHODS: Gastric toxicity was studied in the rat by measuring gastric potential difference and mucosal lesions. Celecoxib was administered intragastrically, either in basal conditions or in combination with damaging (acetylsalicylic acid and ethanol) or protective (sodium nitroprusside and lipopolysaccharides from Escherichia coli) agents. The anti-inflammatory activity was evaluated in the carrageenan-induced paw oedema assay. The non-selective inhibitors indomethacin and acetylsalicylic acid were used for comparison. RESULTS: In conscious rats celecoxib, indomethacin and acetylsalicylic acid significantly reduced the paw oedema induced by carrageenan. While acetylsalicylic acid and indomethacin significantly reduced basal gastric potential difference and caused gastric mucosal lesions, celecoxib was ineffective; moreover, it did not aggravate the direct damaging effect of intragastric ethanol or aspirin. Pretreatment with the non-selective nitric oxide synthase inhibitor N-nitro-L-argynine methyl ester did not significantly change the gastric effects of celecoxib. Both celecoxib and indomethacin prevented the gastroprotective effects induced by sodium nitroprusside (nitric oxide donor) or by bacterial lipopolysaccharides (inducer of nitric oxide synthesis). CONCLUSIONS. These data indicate that the selective cyclooxygenase-2 inhibitor celecoxib did not alter gastric mucosal barrier nor induced mucosal lesions in the healthy or nitric oxide-deficient rat gastric mucosa. However, cyclooxygenase-2 inhibition impaired nitric oxide-dependent gastroprotection, indicating that cyclooxygenase-2 derived prostaglandins may be involved in the gastric mucosal defence.

Gastroprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible gastric nitric oxide synthase.

BACKGROUND: The novel non-steroidal anti-inflammatory drug amtolmetin guacyl has been shown to possess markedly reduced ulcerogenic effects and nitric oxide-mediated gastroprotective activity against the damage induced by ethanol in the rat. AIMS: To investigate, in the rat, the role of nitric oxide and of inducible nitric oxide synthase isoform in the protective effect of amtolmetin guacyl against the gastric damage induced by ethanol. METHODS: The effects of amtolmetin guacyl on gastric transmucosal potential difference and on gastric mucosal blood flow were investigated in the anaesthetised rat; myeloperoxidase activity, inducible and endothelial nitric oxide synthase protein content were determined in rat gastric mucosal homogenates. The anti-inflammatory drug tolmetin and the bacterial lipopolysaccharide from Escherichia coli were studied for comparison. RESULTS: In the anaesthetised rat, amtolmetin guacyl, but not tolmetin, reduced by approximately 50% the fall in gastric potential difference and, to a lesser extent, the macroscopic damage induced by ethanol. The effect of amtolmetin guacyl on transmucosal potential difference was prevented by the selective inducible nitric oxide synthase inhibitor 1400W. In amtolmetin guacyl-treated rats, 1400W decreased gastric mucosal blood flow, whereas it was inactive in vehicle- and tolmetin-treated animals. In gastric mucosal homogenates, both amtolmetin guacyl and lipopolysaccharide, but not tolmetin, increased inducible, but not endothelial, nitric oxide synthase protein content, as revealed by Western immunoblotting. CONCLUSIONS: These data confirm that amtolmetin guacyl is a non-steroidal anti-inflammatory agent devoid of gastrolesive properties, that can actually reduce the damaging effects of ethanol through the increase in nitric oxide production, via the inducible isoform of nitric oxide synthase.

Gastrosparing effect of new antiinflammatory drug amtolmetin guacyl in the rat: involvement of nitric oxide.

The effect of the nonsteroidal antiinflammatory drug (NSAID) amtolmetin guacyl (AMG) on the gastric mucosa was studied in the rat by means of histological and functional techniques. AMG administered at 50-300 mg/kg intragastrically was virtually devoid of gastrolesive properties after either acute or repeated treatment. By contrast, its metabolite, tolmetin (TOL, 15-60 mg/kg, intragastrically) caused dose-dependent gastric damage after both treatments. Light and electron microscopy revealed that AMG induced minimal changes in the surface epithelium layer, without signs of vasocongestion or leukocytes adherence. AMG (50 mg/kg intragastrically) did not change basal gastric potential difference (PD), whereas acetylsalicylic acid and ibuprofen induced falls in PD of 22 and 27 mV, respectively. AMG (50 mg/kg intragastrically) reduced by 60% the fall in PD induced by 50% ethanol; this inhibition was dependent on the incubation time, and was maximal when AMG was given 4 hr before ethanol. AMG (100 mg/kg intragastrically) induced an increase in NO synthase type 2 (NOS2) activity, which was significantly different from control values, when AMG was administered 4 hr before the test. The metabolites of AMG, tolmetin, MED 5, and guaiacol were ineffective. Pharmacokinetic analysis of the residence time of AMG in the different areas of the gastrointestinal tract, revealed that AMG remains in the gastrointestinal tract at least for 4 hr, the time necessary for a maximal induction of NOS2 and for maximal protection against ethanol-induced damage. In conclusion, these data indicate that the nonsteroidal antiinflammatory drug amtolmetin guacyl is devoid of gastrolesive properties; this gastro-sparing effect seems to involve the production of nitric oxide, which can counteract the damaging effects due to prostaglandin inhibition. The presence in the stomach of the native molecule of amtolmetin guacyl seems to be necessary for the protective effect observed.

Effects of histamine H2 receptor agonists and antagonists on the isolated guinea pig gallbladder.

Histamine H2 receptor-mediated responses were examined on cholecystokinin-octapeptide (CCK-8)-precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H2 receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H2 receptor-mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H2 receptor antagonist mepyramine (10 microM), and the H2 receptor agonists dimaprit, impromidine and amthamine, inhibited CCK-8 (3 nM)-induced contractions in a concentration-dependent fashion, with the following rank orders of potency: impromidine > amthamine > histamine > dimaprit (pD2 values were 6.73 +/- 0.04, 5.44 +/- 0.07, 4.64 +/- 0.04 and 3.71 +/- 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and amthamine, which behaved as full agonists. All the H2 receptor antagonists examined were able to inhibit amthamine-induced relaxation. Famotidine (pA2 = 7.09 +/- 0.26), zolantidine (pA2 = 6.54 +/- 0.11), compound SKF 92857 (pA2 = 6.58 +/- 0.13) and aminopotentidine (pA2 = 6.86 +/- 0.06) competitively antagonised the amthamine-induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations (1 microM, pA2 = 6.83 +/- 0.21). Finally, the slowly-dissociable antagonist loxtidine caused a non-parallel displacement to the right of the concentration--response curve to amthamine (pKB = 7.55 +/- 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 microM). In conclusion, histamine H2 receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H2 receptors in different experimental models.

Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat.

The effect of the cannabinoid (CB) receptor agonist WIN 55,212-2 on gastric acid secretion was studied in the anaesthetized rat after stimulation with pentagastrin. WIN 55,212-2 (0.5-2 mg/kg, i.v.) was inactive on basal secretion but caused a marked inhibition (80%) of the acid secretion stimulated by pentagastrin (10 microg/kg, i.v.). The enantiomer WIN 55,212-3 (1-3 mg/kg, i.v.) did not significantly modify basal or pentagastrin-induced acid secretion. The inhibitory effect of WIN 55,212-2 against pentagastrin was prevented by the administration of the selective cannabinoid CB1 receptor antagonists SR141716A (1 mg/kg, i.v.) and LY320135 (1 mg/kg, i.v.); by contrast, the CB2 receptor antagonist SR144528 (0.3-1 mg/kg, i.v.) was without effect. The selective CB2 receptor agonist JWH-015 (0.1-10 mg/kg, i.v.) was inactive on the increase of acid output stimulated by pentagastrin. These results suggest that the inhibitory effect of WIN 55,212-2 on pentagastrin-stimulated acid secretion in the anaesthetized rat is mediated by specific cannabinoid receptors. Moreover, the antagonism of WIN 55,212-2-induced effects by the selective CB1 receptor antagonists SR141716A and LY320135 together with the ineffectiveness of both the CB2 receptor agonist JWH-015 and the CB2 receptor antagonist SR144528 indicate that CB1 receptor subtypes are predominantly involved in the antisecretory effect of WIN 55,212-2.

The contractile effect of fedotozine on guinea pig isolated intestinal cells is not mediated by kappa opioid receptors.

The compound fedotozine, recently described as a peripheral kappa opioid receptor agonist, was tested on smooth muscle cells isolated from the longitudinal muscle layer of the guinea pig ileum, in comparison with the selective kappa receptor agonist, compound U-50488. Fedotozine (1 nmol/l-1 micromol/l) caused a concentration-dependent contraction of intestinal cells, with a maximum decrease in cell length not significantly different from that caused by acetylcholine. The kappa agonist U-50488 (0.1 pmol/l-100 nmol/l) was without effect. The contractile effect of fedotozine was not significantly modified by naloxone (0.1-1 micromol/l). These results indicate that fedotozine can have direct excitatory effects on intestinal smooth muscle cells from the guinea pig ileum not mediated by activation of kappa opioid receptors.

Effects of different antisecretory drugs on gastric potential difference in the rat: comparison with sucralfate.

The proton pump inhibitors omeprazole and lansoprazole and the histamine H2 receptor antagonists ranitidine and nizatidine were investigated for their effects on gastric transmucosal potential difference (PD) in the rat, in comparison with the gastroprotective compound sucralfate. Omeprazole (1-3 mg kg-1, i.v.) and lansoprazole (1-3 mg kg-1, i.v.) did not modify basal PD, but significantly reduced (by approx. 50-60%) the drop in PD caused by intragastric administration of acetylsalicylic acid (ASA, 60 mg kg-1). Ranitidine (3-100 mg kg-1, i.v.) and nizatidine (10-30 mg kg-1, i.v.) behaved similarly to proton pump inhibitors, being ineffective on basal PD, while significantly reducing the effect of ASA. The antisecretory compounds did not change basal pH values. Sucralfate (0.5-1.5 g kg-1 intragastrically) caused a slight increase (approx. 20%) of basal PD and a dose-dependent reduction of ASA-induced fall in PD, with a maximum effect (65% reduction) comparable to that caused by the antisecretory agents. These results showed that ASA-induced disruption of the mucosal barrier can be reduced to the same extent by various antiulcer drugs, irrespective of their effects on gastric acid secretion.