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The features of reserpine-induced gastric mucosal lesions.

ABSTRACT: AIM: To reinvestigate the characteristics of reserpine-induced gastric mucosal lesions (GMLs). METHODS: The GML-inducing effect of reserpine and the time-course of recovery from reserpine-induced GMLs were examined in Sprague-Dawley (SD) rats. The GML-inducing and blood pressure-decreasing effects of Compound Hypotensive Tablets (CHTs) were investigated in spontaneously hypertensive rats (SHRs). Intracerebroventricular (icv) injection and vagotomy were performed to verify the central vagal mechanism in reserpine-induced GMLs. RESULTS: Single intraperitoneal (ip) injections of reserpine (0.25, 0.5, 1, 2, 4, and 6 mg/kg) dose-dependently induced GMLs in SD rats. Both single and repeated (2 weeks) oral administrations of reserpine led to slight GMLs at doses of 24 mg/kg and 10 mg/kg, respectively. Blood pressure was significantly decreased in SHRs after 2 months of CHT administration (0.01 and 0.03 mg/kg; doses were expressed as the amount of reserpine in the CHT). CHT doses of 0.3 mg/kg induced GMLs, but 0.1 mg/kg did not. Examining the time course of recovery from GMLs, severe GMLs occurred 18 h after ip reserpine (4 mg/kg), obviously lessened at 1 week and healed spontaneously at 3 weeks. Intracerebroventricular injections of reserpine caused GMLs at much lower doses (0.08 and 0.4 mg/kg), and reserpine-induced GMLs were greatly inhibited by vagotomy, suggesting the involvement of a central vagal mechanism. CONCLUSION: Reserpine-induced GMLs were dose-dependent, and the lesions healed spontaneously within 3 weeks. Long-term treatment with CHT at doses adequate to decrease blood pressure will not induce GMLs. A central vagal mechanism was involved in reserpine-induced GMLs.

SUBMITTER: Ma XJ

PROVIDER: S-EPMC4007818 | biostudies-other | 2010 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundCurrent knowledge about clinical and genetic risk factors for aspirin-induced gastric mucosal injury is not sufficient to prevent these gastric mucosal lesions.MethodsWe recruited aspirin takers as the exposed group and healthy volunteers as the control group. The exposed group was categorized into two subgroups such as subgroup A as gastric mucosal injury diagnosed by gastroscopy, including erosion, ulcer or bleeding of the esophagus, stomach, or duodenum; subgroup B as no injury of the gastric mucosa was detected by gastroscopy. Clinical information was collected, and 53 single nucleotide polymorphisms were evaluated.ResultsAmong 385 participants, 234 were in the aspirin-exposed group. According to gastroscopy, 82 belonged to subgroup A, 91 belonged to subgroup B, and gastroscopic results of 61 participants were not available. Using the Chi-square test and logistic regression, we found that peptic ulcer history (odds ratio [OR] = 5.924, 95% confidence intervals [CI]: 2.115-16.592), dual anti-platelet medication (OR = 3.443, 95% CI: 1.154-10.271), current Helicobacter pylori infection (OR = 2.242, 95% CI: 1.032-4.870), male gender (OR = 2.211, 95% CI: 1.027-4.760), GG genotype of rs2243086 (OR = 4.516, 95% CI: 1.180-17.278), and AA genotype of rs1330344 (OR = 2.178, 95% CI: 1.016-4.669) were more frequent in subgroup A than subgroup B. In aspirin users who suffered from upper gastrointestinal bleeding, the frequency of the TT genotype of rs2238631 and TT genotype of rs2243100 was higher than in those without upper gastrointestinal bleeding.ConclusionsPeptic ulcer history, dual anti-platelet medication, H. pylori current infection, and male gender were possible clinical risk factors for aspirin-induced gastric mucosal injury. GG genotype of rs2243086 and AA genotype of rs1330344 were possible genetic risk factors. TT genotype of rs2238631 and TT genotype of rs2243100 may be risk factors for upper gastrointestinal bleeding in aspirin users.

Project description:Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide and other bioactive lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor, URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent pain. When administered by the oral route in mice, URB937 was highly active (median effective dose, ED(50), to inhibit liver FAAH activity: 0.3mgkg(-1)) and had a bioavailability of 5.3%. The antinociceptive effects of oral URB937 were investigated in mouse models of acute inflammation (carrageenan), peripheral nerve injury (chronic sciatic nerve ligation) and arthritis (complete Freund's adjuvant). In all models, URB937 was as effective or more effective than standard analgesic and anti-inflammatory drugs (indomethacin, gabapentin, dexamethasone) and reversed pain-related responses (mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia) in a dose-dependent manner. ED(50) values ranged from 0.2 to 10mgkg(-1), depending on model and readout. Importantly, URB937 was significantly more effective than two global FAAH inhibitors, URB597 and PF-04457845, in the complete Freund's adjuvant model. The effects of a combination of URB937 with the non-steroidal anti-inflammatory agent, indomethacin, were examined in the carrageenan and chronic sciatic nerve ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate pain-related behaviors. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory pain. Our findings further suggest that FAAH and cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other's actions.

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The features of reserpine-induced gastric mucosal lesions.

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