Gastric effects of the novel non-steroidal anti-inflammatory drug amtolmetin guacyl.
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Animals↗
Biomedical subjects
G Coruzzi
Publications and source records attributed to G Coruzzi.
Gastric antisecretory effects of compound BP 2-94: a histamine H3-receptor agonist prodrug.
Compound BP 2-94 is an orally available prodrug of the histamine H3-receptor agonist (R)-alpha-methylhistamine, which was found to produce higher plasma levels than the parent drug in humans. In the present study radioimmunoassay was carried out in dogs to investigate the generation of (R)-alpha-methylhistamine in vivo after intragastric administration of the prodrug. The effects of BP 2-94 on gastric acid secretion and on histamine, gastrin, and somatostatin release were also investigated. After intragastric administration of BP 2-94 (10 mg/kg), both the prodrug and (R)-alpha-methylhistamine were detected in plasma: plasma levels of (R)-alpha-methylhistamine decayed with a T1/2 of about 1 hr and displayed concentrations as high as 50-fold the EC50 of the drug at the H3 receptor for at least 2 hr. In conscious dogs provided with gastric fistula BP 2-94, administered at 10 and 30 mg/kg intragastrically, caused a dose-dependent inhibition (maximum reduction was about 80%) of the acid secretion stimulated by 2-deoxy-D-glucose, whereas (R)-alpha-methylhistamine (20 mg/kg, intragastrically) was ineffective. BP 2-94 (30 mg/kg, intragastrically) significantly reduced the acid secretion stimulated by bombesin, while leaving unaffected that induced by histamine. The increase in plasma gastrin levels induced by 2-deoxy-D-glucose, bombesin or a test meal was not significantly modified by BP 2-94 (30 mg/kg, intragastrically). In anesthetized dogs BP 2-94 (30 mg/kg, intragastrically) significantly reduced histamine release detected in the portal vein under bombesin infusion, whereas it did not modify gastrin and somatostatin plasma levels. These data indicate that BP 2-94 is a good prodrug of (R)-alpha-methylhistamine in the dog, causing an efficacious reduction of acid secretion induced by both 2-deoxy-D-glucose and bombesin. Moreover, the study of paracrine and hormonal mediators of acid secretion confirms that the main mechanism underlying inhibition of acid production induced by H3-receptor activation is the impairment of histamine release from gastric histaminocytes (possibly enterochromaffin-like cells).
Animals↗
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.
Animals↗
Molecular evolution of glutamate receptors: a primitive signaling mechanism that existed before plants and animals diverged.
We performed a genealogical analysis of the ionotropic glutamate receptor (iGluR) gene family, which includes the animal iGluRs and the newly isolated glutamate receptor-like genes (GLR) of plants discovered in Arabidopsis. Distance measures firmly placed the plant GLR genes within the iGluR clade as opposed to other ion channel clades and indicated that iGluRs may be a primitive signaling mechanism that predated the divergence of animals and plants. Moreover, phylogenetic analyses using both parsimony and neighbor joining indicated that the divergence of animal iGluRs and plant GLR genes predated the divergence of iGluR subtypes (NMDA vs. AMPA/KA) in animals. By estimating the congruence of the various glutamate receptor gene regions, we showed that the different functional domains, including the two ligand-binding domains and the transmembrane regions, have coevolved, suggesting that they assembled together before plants and animals diverged. Based on residue conservation and divergence as well as positions of residues with respect to functional domains of iGluR proteins, we attempted to examine structure-function relationships. This analysis defined M3 as the most highly conserved transmembrane domain and identified potential functionally important conserved residues whose function can be examined in future studies.
Amino Acid Sequence↗
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.
Animals↗
Glutamate-receptor genes in plants.
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Amino Acid Sequence↗
A PII-like protein in Arabidopsis: putative role in nitrogen sensing.
PII is a protein allosteric effector in Escherichia coli and other bacteria that indirectly regulates glutamine synthetase at the transcriptional and post-translational levels in response to nitrogen availability. Data supporting the notion that plants have a nitrogen regulatory system(s) includes previous studies showing that the levels of mRNA for plant nitrogen assimilatory genes such as glutamine synthetase (GLN) and asparagine synthetase (ASN) are modulated by carbon and organic nitrogen metabolites. Here, we have characterized a PII homolog (GLB1) in two higher plants, Arabidopsis thaliana and Ricinus communis (Castor bean). Each plant PII-like protein has high overall identity to E. coli PII (50%). Western blot analyses reveal that the plant PII-like protein is a nuclear-encoded chloroplast protein. The PII-like protein of plants appears to be regulated at the transcriptional level in that levels of GLB1 mRNA are affected by light and metabolites. To initiate studies of the in vivo function of the Arabidopsis PII-like protein, we have constructed transgenic lines in which PII expression is uncoupled from its native regulation. Analyses of these transgenic plants support the notion that the plant PII-like protein may serve as part of a complex signal transduction network involved in perceiving the status of carbon and organic nitrogen. Thus, the PII protein found in archaea, bacteria, and now in higher eukaryotes (plants) is one of the most widespread regulatory proteins known, providing evidence for an ancestral metabolic regulatory mechanism that may have existed before the divergence of these three domains of life.
Amino Acid Sequence↗
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.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Effects of beta3-adrenoceptor agonist SR 58611A on gastric acid secretion and histamine release in the dog: comparison with ritodrine.
1. The involvement of beta3 adrenoceptors in the control of gastric acid secretion and histamine release was investigated in the dog. 2. In conscious dogs, SR 58611A (0.0625-1.0 mg/kg/hr i.v.) dose dependently inhibited gastric acid secretion induced by pentagastrin. Maximal inhibition (40%) was obtained with the dose of 1 mg/kg. Ritodrine (1 mg/kg/hr i.v.) also induced a marked inhibition (85%) of gastric acid secretion stimulated by pentagastrin. 3. On 2-deoxy-D-glucose-stimulated acid secretion, both SR 58611A and ritodrine at 1 mg/kg/hr i.v. showed inhibitory effects. On these experiments, ritodrine, but not SR 58611A, significantly reduced plasma gastrin concentrations. 4. In anaesthetized dogs, histamine concentrations from gastrosplenic vein increased fivefold after the infusion of pentagastrin. SR 58611A (1 mg/kg/hr i.v.) did not significantly modify the stimulant effect of pentagastrin on histamine release. In contrast, ritodrine (1 mg/kg/hr i.v.) significantly inhibited histamine release induced by pentagastrin. 5. These data suggest that beta3 adrenoceptors may participate in the negative control of gastric acid secretion in the dog, probably through a histamine-independent mechanism.
Adrenergic beta-Agonists↗
Histamine receptor-independent muscle relaxation elicited by a series of histamine H2-receptor agonists on the isolated guinea pig duodenum: a study into the mechanism of action.
1. The histamine H2 receptor agonists, dimaprit, impromidine, amthamine, and several dimaprit- and impromidine-analogues were investigated for their spasmolytic activity on the guinea pig duodenum, precontracted with acetylcholine or KCl. 2. Almost all the H2 receptor agonists exerted a histamine H2 receptor-independent muscle relaxation, which was more evident on acetylcholine- than on KCl-precontracted preparations. 3. The relaxing activity of these compounds was independent of inhibitory receptors, like beta-adrenergic, GABA-ergic, serotoninergic, etc. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of histamine H2-receptor agonists was shared only by the Na+-blocker procaine, the intracellular Ca2+-antagonist ruthenium red and, at least in terms of efficacy, by the protein kinase C inhibitor, chelerithrine. 5. This spasmolytic effect is probably due to an impairment of receptor-mediated depolarization at the plasma membrane level and/or an inhibitory activity on the protein kinase C-dependent activation of the contractile machinery. 6. Finally, our findings suggest that the histamine H2 receptor-independent muscle relaxation is a general feature shown by H2 receptor agonists endowed with different chemical structure and the putative spasmolytic "receptor" prefers a (substituted) thiazole over a (substituted) imidazole.
Animals↗
Reciprocal regulation of distinct asparagine synthetase genes by light and metabolites in Arabidopsis thaliana.
In plants, the amino acid asparagine serves as an important nitrogen transport compound whose levels are dramatically regulated by light in many plant species, including Arabidopsis thaliana. To elucidate the mechanisms regulating the flux of assimilated nitrogen into asparagine, we examined the regulation of the gene family for asparagine synthetase in Arabidopsis. In addition to the previously identified ASN1 gene, we identified a novel class of asparagine synthetase genes in Arabidopsis (ASN2 and ASN3) by functional complementation of a yeast asparagine auxotroph. The proteins encoded by the ASN2/3 cDNAs contain a Pur-F type glutamine-binding triad suggesting that they, like ASN1, encode glutamine-dependent asparagine synthetase isoenzymes. However, the ASN2/3 isoenzymes form a novel dendritic group with monocot AS genes which is distinct from all other dicot AS genes including Arabidopsis ASN1. In addition to these distinctions in sequence, the ASN1 and ASN2 genes are reciprocally regulated by light and metabolites. Time-course experiments reveal that light induces levels of ASN2 mRNA while it represses levels of ASN1 mRNA in a kinetically reciprocal fashion. Moreover, the levels of ASN2 and ASN1 mRNA are also reciprocally regulated by carbon and nitrogen metabolites. The distinct regulation of ASN1 and ASN2 genes combined with their distinct encoded isoenzymes suggest that they may play different roles in nitrogen metabolism, as discussed in this paper.
Amino Acid Sequence↗
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.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Histamine H3 Receptors and Gastric Acid Secretion.
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Journal Article↗
Histamine H3 receptors and gastric acid secretion.
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Animals↗
The beta3-adrenoceptor agonist SR58611A inhibits gastric acid secretion in the conscious cat.
The effect of the beta3-adrenoceptor agonist [ N-[(2S)-7-ethoxycarbonyl-methoxyl-1,2,3,4-tetrahydronaphth-2-yl] (2R)-2-(3-chloro-phenyl)2-hydroxyethanamine hydrochloride] (SR58611A) on gastric acid secretion was investigated in conscious cats with a gastric fistula. Intravenous infusion of SR58611A (0.3-3 micromol/kg/h) caused a dose-dependent inhibition of the acid secretion stimulated by 2-deoxy-D-glucose (2DG), with a maximum reduction by 45%. The secretory effect of the histamine H2-receptor agonist dimaprit only tended to be reduced by SR58611A (3 micromol/kg/h). The inhibitory effect of SR5861 IA was not modified by the non selective beta1- and beta2-adrenoceptor antagonist propranolol (1.5 micromol/kg i.v.), but it was prevented by bupranolol (10 micromol/kg i.v.), a drug endowed with beta3-antagonistic properties. Both antagonists blocked the inhibitory effect of the beta2-adrenoceptor agonist clenbuterol (0.1 micromol/kg/h) on 2DG-induced acid secretion. These findings suggest that compound SR58611A inhibits gastric acid secretion in the conscious cat through activation of beta3-adrenoceptors insensitive to propranolol.
Adrenergic beta-Agonists↗
Contractile and relaxant effects of dimaprit on guinea pig isolated intestinal cells.
The effect of the histamine H2 receptor agonist dimaprit on intestinal contractility was characterized on smooth muscle cells isolated from the longitudinal muscle of the guinea pig ileum. Dimaprit exerted two opposite effects on the contractility of isolated muscle cells: relaxation of cholecystokinin octapeptide (CCK-8)-induced contractions in the range of concentrations 10(-17)-10(-13) M and contraction at concentrations higher than 10(-13) M. The relaxant effect of dimaprit was totally prevented by the H2 blocker famotidine (10(-7) M), which, at the same time, enhanced the contractile effect of dimaprit, shifting to the left the concentration-response curve to the agonist. This contraction was not modified by the histamine H1 receptor antagonists pyrilamine and temelastine, tested both at 10(-7) M. By contrast, atropine 10(-8) M abolished the contractile effect of dimaprit, while leaving unchanged the response to CCK-8. Our results clearly indicate that longitudinal muscle cells of the guinea pig ileum possess inhibitory H2 receptors, which can be activated by very low concentrations of dimaprit; moreover, they revealed that dimaprit can have non-histaminergic effects, probably due to muscarinic receptor activation; however, concentrations about 10000 times higher than those necessary to activate H2 receptors, are required.
Animals↗
Light-induced transcriptional repression of the pea AS1 gene: identification of cis-elements and transfactors.
Here, we examine the cis-elements and trans-factors affecting the expression of asparagine synthetase (AS) genes whose transcription is negatively regulated by light. The promoters for the AS1 and AS2 genes of pea were isolated, sequenced, and functionally dissected for their ability to confer regulated expression to the GUS reporter gene in transgenic tobacco. Histochemical analysis of transgenic plants demonstrated that the AS1 and AS2 promoters show identical patterns of cell-specific expression. The more highly active AS1 promoter was further demonstrated to confer negative light-regulation to the GUS gene in transgenic tobacco. Deletion analysis and gain-of-function experiments showed that 124 bp of the AS1 promoter was sufficient to confer light-activated repression to a heterologous promoter. Potential conserved transcription regulatory elements, Box B, Box C, and Box C' within this region were shown to bind to nuclear proteins by gel shift analysis. A light-specific DNA:protein interaction was detected with Box B. The nuclear factors that bind to Box C and C' elements of AS1 are competed by a putative repressor element 'RE1' defined previously in the oat phytochrome gene whose transcription is also repressed by light. The Box B and C/C'-Box/RE1-binding factors were found in nuclear extracts of tobacco, pea, and Arabidopsis and may therefore be universal factors involved in light-activated transcriptional repression.
Aspartate-Ammonia Ligase↗
Mixed antisecretory and gastroprotective activities of a new H2-antagonist containing a nitric oxide-donor furoxan moiety.
The effect of a new histamine H2-receptor antagonist derived from the lamtidine molecule and containing a nitric oxide (NO)-donor furoxan moiety (derivative 1) was studied for its gastric antisecretory activity and for a possible gastroprotective effect, in comparison with the analog without the furoxan moiety (derivative 2). The H2-receptor antagonistic activity was also investigated in the isolated guinea pig papillary muscle. Derivative 1 was approximately 10 times less potent than derivative 2 at the H2-receptor level; conversely, it was about 10 times more effective as a gastroprotective agent against ethanol- and 0.6 N HCl-induced gastric lesions. The mechanism of the gastroprotection exerted by derivative 1 is probably connected with the release of NO, whose vasodilating action on gastric mucosa vessels is crucial. The combined antisecretory and gastroprotective activity of derivative 1 allows this compound to be considered as a prototype of a new class of antiulcer agents.
Animals↗