A Mongolian gerbil model was used to clarify whether long-term colonization by Helicobacter pylori is an important risk factor for the development of gastric cancer. Fifty-nine gerbils (3 controls and 56 gerbils inoculated with H. pylori) were killed at various times (average, 23 months) more than 12 months after H. pylori inoculation. In the H. pylori-inoculated group, poorly differentiated adenocarcinoma was observed in the pylorus of 1 gerbil, and carcinoid was observed in the fundus of the stomach in 18 gerbils. No lesions were found in the stomachs of the 3 control gerbils. The results imply that long-term colonization by H. pylori is an important risk factor for the development of gastric adenocarcinoma and carcinoid.
Ondansetron (10 mgkg, p.0.) and granisetron (1 mgkg, p.0.) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s .~) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mgkg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mgkg, P.o.), trimebutine (300 mgkg, P.o.), and metoclopramide (30 mgkg, p.0.) did not. Azasetron (10 pg) administered intracerebroventricularly did not inhibit the stressinduced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit partic- ularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in strewrelated colonic dysfunction like irritable bowel syndrome.
Effects of the amount and the composition of meals on gastric emptying and small intestinal transit times of a suspension were investigated in beagle dogs using acetaminophen and salicylazosulfapyridine as markers. Gastric emptying time was affected both by the amount and the composition of a meal; it was prolonged proportionally to the amount of a solid meal and varied among the 3 kinds of test meals of the same energy content in the following rank order: lard greater than skimmed milk greater than mashed potatoes. The inter-individual variation of small intestinal transit time in a fed state was smaller than that in a fasted state, whereas the mean transit times in both states were similar. Small intestinal transit time was not affected by the amount of the solid meal. On the other hand, it varied among the 3 kinds of test meals in the following rank order: lard greater than mashed potatoes greater than skimmed milk. It is noteworthy that small intestinal transit time in the beagle dog is approximately 2 h shorter than that in humans both in fasted and fed states.
-Monkey cerebral artery strips partially contracted with prostaglandin F2a responded to histamine with biphasic patterns of relaxation. The delayed and sustained relaxation was suppressed by cimetidine, whereas the phasic response was abolished by treatment with chlorpheniramine and NG nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor. The inhibition by L-NA was reversed by L-arginine. D-NA was without effect. Endothelium denudation abolished the phasic relaxation. We hypothesized that endothelium-dependent, phasic relaxations caused by histamine are mediated by NO that is released by Hi-receptor stimulation, whereas the sustained relaxation is associated with the activation of H2-receptors in the smooth muscle of monkey cerebral arteries.Keywords: Histamine, Nitric oxide, Endothelium, Hi-receptor subtype, Cerebral artery (monkey)The complexity of vascular responses to histamine is based on its actions on histaminergic receptor subtypes, H1 and H2, in the endothelium and smooth muscle and on the release of chemical mediators, such as endothelium-derived relaxing factor (EDRF) and pros taglandins (PGs), from endothelial and subendothelial tissues (1 6). Histamine-induced relaxations mediated by EDRF have been reported in human, monkey and rabbit cerebral arteries (7, 8); human and monkey coronary arteries (9, 10); guinea pig pulmonary arteries (11); human umbilical vessels (12); monkey pulmonary veins (13); and rat aortas (14). The participation of EDRF is postulated from evidence that the relaxation is dependent on the endothelium and is suppressed by treatment with oxyhemoglobin, methylene blue or anti oxidants. EDRF has been proposed to be nitric oxide (NO) or an unstable S-nitroso compound that releases the NO radical (15, 16). However, endothelium-depend ent relaxations are not always associated with NO or its analog (17, 18).We have reported that endothelium-dependent re laxations caused by histamine in monkey cerebral arter ies are significantly inhibited by methylene blue and chlorpheniramine, suggesting the involvement of the endothelial H1-receptor subtype in the release of EDRF (7). Despite this conclusion, whether NO was actually involved in the response could not be determined. Methylene blue has many actions other than the inhibi tion of soluble guanylate cyclase (19,20), whereas NO synthase inhibitors, including NG-monomethyl-L-argi nine, NG-nitro-L-arginine (L-NA), L-NA methylester, etc. (21), are selective in depressing the synthesis of NO. Thus, the role of NO can be evaluated more speci fically by the use of these inhibitors. In addition, the effectiveness of NO synthase inhibitors on the endo thelium-dependent relaxation has not been evaluated in cerebral arteries.Therefore, the present study was undertaken to eluci date the involvement of endothelium-derived NO in the histamine-induced relaxation of isolated monkey cere bral arteries, with special reference to the histaminergic receptor subtypes. MATERIALS AND METHODS PreparationJapanese monkeys (Macaca fuscata) of eith...
ABSTRACT-This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl )-6-chloro-4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazine-8-carbox amide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 re ceptors at the synaptic membranes of the rat cerebral cortex with a K; value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine Hl receptors (IC50 = 4.4,uM) but it could not reveal any affinities for the other receptors (5 HT1A, 5-HT2, dopamine D1, dopamine D2, a1-adrenoceptor, a2-adrenoceptor, muscarine and benzo diazepine) even at a 10 ,u M concentration. In the isolated rabbit heart, Y-25130 antagonized the in direct sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.Keywords: Y-25130, 5-HT3 receptor, Heart (isolated), Ileum (isolated) Gaddum and Picarelli (1) reported that 5-hydroxy tryptamine (5-HT) induces contractions in the guinea pig ileum in vitro by activating two distinct 5-HT recep tor subtypes: the neuronal `M' receptor and the `D' re ceptor located on the longitudinal smooth muscle, sub sequently referred to as 5-HT3 and 5-HT2 receptors, re spectively (2).Selective 5-HT3 receptor antagonists such as ondan setron (3) and granisetron (4) have been developed and are now used clinically for the prevention of chemo therapy-induced nausea and vomiting.Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4 methyl-3 -oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carbox amide monohydrochloride) is now being developed as an antiemetic drug for the prevention of emesis induced by anticancer therapy. According to Fukuda et al. (5), Y 25130 was effective against emesis induced in dogs and ferrets by cytotoxic drugs or by total body irradiation. It has been subsequently reported that Y-25130 is a po tent inhibitor of the von Bezold-Jarisch effect induced by 5-HT or 2-methyl-5-HT in rats (6). The von Bezold Jarisch effect is thought to be induced by activation of 5-HT3 receptors on sensory vagal afferents (2). Recent ly, Richardson and Engel (7) have reported 5-HT3 re ceptor antagonism in different bioassay systems.The purpose of this study is to examine the antago nistic activities of Y-25130 on 5-HT3 receptors in vitro. The interaction of Y-25130 with 5-HT3 receptor...
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