A1244 AGA ABSTRACTS

5693

GASTROESOPHAGEAL REFLUX DISEASE IN DIABETES:CHARACTERISTICS AND TREATMENT WITH RABEPRAZOLE.Noriyuki Hasegawa, Taku Watanabe, Hikaru Tanaka, Jun Matsui, YoshijiOgawa, Teruo Nakamura, Hiroaki Kikuchi, Tadashi Takeuchi, HirosakiUniv Sch of Medicine, Hirosaki, Japan; Tokyo Women's Med Univ,Tokyo, Japan.

Objective: Long-standing diabetes can lead to chronic complications in­cluding diabetic autonomic neuropathy, which causes diabetic gastrointes­tinal dysfunction associated with various symptoms and conditions of thedigestive system. In this study, we tried to clarify the characteristics ofdiabetes-related GERD (gastroesophageal reflux disease) and the effect ofrabeprazole, a new proton pump inhibitor, using gastroesophageal pHmonitoring. Subjects and Methods: Upper gastrointestinal endoscopy and24-hour gastroesophageal pH monitoring were performed on 16 patientswith diabetes. An esophageal pH sensor was placed approximately 5 cmfrom the lower esophageal sphincter. GERD was defined, based on endo­scopic findings or a frequency of pH:54.0 greater than 4% of the 24 hours.In addition, gastric emptying was measured using DC-acetate. Other com­plications of diabetes in these patients were also assessed. Results: Nine of16 patients had GERD. The average age of the patients with GERD was56.9 years; the average duration of diabetes was 9.8 years. Other compli­cations of diabetes in these patients included neuropathy in 7, retinopathyin 6 and nephropathy in 5. Gastric emptying was almost delayed. Thefrequency of the acid reflux in the upright posture was significantly greaterin the patients with GERD (upright 81±12% vs. supine20± 12%,p=O.0001 ). The subjective symptoms of reflux were found in 5patients with GERD, these were significantly improved in all cases afterrabeprazole administration. Moreover, when rabeprazole was administeredto 4 patients who had no subjective symptoms, the quality of life improvedin 3. The time pH:54.0 was averaged 43%, before rabeprazole administra­tion and it improved after administration to 8%(p=0.OOOI). Conclusion:The characteristics of GERD in patients with diabetes is that the acid refluxis more frequent in upright posture, and that a subjective and objectiveimprovement is seen in this disease with the administration of rabeprazole.

5694ULTRASTRUCTURAL EVALUATION OF APOPTOSIS INDUCEDBY HELlCOBACTER PYLORI INFECTION IN GASTRIC MUCO­SA: THE NOVEL REMARKS ON LAMINA PROPRIA MUCOSAE.Chikako Hasegawa, Myota Miura, Tomomi Ihara, Masao Sugamata, Deptof Path, Omori Hosp, Toho Univ, Sch of Med, Tokyo, Japan; Dept of Path,Tochigi Institute of Clin Pathology, Tochigi, Japan.

Backgrounds.It has been considered that gastric and duodenal ulcer areinduced by Helicobacter pylori(Hpylori)infection. Presently.there aremany reports on the relationship between Il.pylori infection and apopto­sis.however.these are mostly focused on epithelium using TUNELmethod.In this study.by examination of lamina propria mucousae.wc eval­uated apoptotic appearance induced by H.pvlori infection ultrastructurally.Methods:Gastric biopsy specimens from 37 cases with Hipvlori infectionand 8 healthy volunteers without infection were examined with light andelectron microscope.and analyzed by TUNEL method.All biopsies wereperformed in the patients after informed consent in accordance with theHelsinki declaration. Results:Electron microscopically,apoptotic appear­ance of fibloblasts and smooth muscle cells exaggerated on Hipylori­infected lamina propria mucosae,although no significant difference wasshowed between Hpylori-infected and non-infected gastric mucosa withTUNEL method.And.apoptotic chenges of inflammatory cells were alsoobserved.the collagen fibers were filamented and absent on lamina propriamucosae. Light microscopically,these area showed edematous changes.Conclusions:1t was considered that the structure of Hpylori-infected gas­tric mucosa is weakened due to apoptotic cellular damages of fibloblastsand smooth muscle cells on lamina propria and absence of collagen fiberswhich support and connect epithelial cells.It is conjectured that thesealterations are involved in exaggerative acid secretion and decrease ofmucus protecting factor which has been already reported,and the severeulcer is formed as the results.

5695RELATION BETWEEN CYCLOOXYGENASE AND ANGIOGE·NETIC FACTORS DURING GASTRIC ULCER HEALING ANDGASTRITIS.Hiroshi Hashimoto, Masumi Akimoto, Mutsuo Shigemoto, Katsuko Ya­mashita, Tokyo Women's Med Univ, Tokyo, Japan.

(Objective) To study the relations between COX-I and COX-2 expressionand factors involved in tissue repair and blood flow regulation in the gastricmucosa (PG 12, and nitric oxide (NO)). (Subjects) We studied gastric ulceron anglus (active stage(GA) .healing stage(GH),scar stage(GS))as well asHelicobacter pylori (Hpj-positive gastritis (gast+) and Hp-negative gas­tritis(gast-) as control. All cases of ulcer were Hp-positive. (Method)Bi­opsy specimens obtained from the ulcer margin in ulcer groups, and thegastric anglus, of lesser curvature in gastritis groups were frozen. ForCOX-I and COX-2, mRNA was measured by RT-PCR. The concentrationof PG 12 was measured by RIA,and NO was measured in terms of NOx byGriess method. (Discussion) The expression of COX-l was dominant ingastritis groups, which had low concentrations of angiogenetic factors. Theexpression of COX-l mRNA was highest in gast+ group, suggesting that

GASTROENTEROLOGY Vol. 118, No.4

COX-I participates in the regulation of PGs production and defensemechanisms. Among the gastric ulcer groups, the GA and GH groups,characterized by active mucosal regeneration and angiogenesis, had in­creased levels of PGs and NO associated with a COX2/1 value of morethan I. In the GH group. the expression of COX-2 was especially high,indicating that COX-2 is dominant during this stage. In the GS group,concentrations of angiogenetic substances were low; the expression ofCOX-2 was also low. These results suggest that angiogenetic factorsinteract with COX-2 during the repair of gastric ulcers, whereas. COX- [plays the dominant role in Hp-positive gastritis.

(Results) GA(n=?) GH(n=10) GS(n= 11) gast+(n=15) gasl·(n=13)

COX·1(mRNA) 096 165 148 2.21 1.05COX·2(mRNA) 100 223 113 148 0.58coxz-ee« 1.28 1.29 077 0.65 057PG12 (pglmg) 18 14 11 12 9NOx(nM) 182 170 82 15 21

5696

EFFECT OF NITRIC OXIDE ON GASTRIC MUCOSAL LESIONSINDUCED BY WATER-IMMERSION·RESTRAINT STRESS.Hiroshi Hashimoto, Akiko Yanagisawa, Masumi Akimoto, Mutsuo Shige­moto, Katsuko Yamashita, Inst of Geriatrics, Tokyo Women's Med Coli,Tokyo. Japan: Institute of Geriatrics, Tokyo Women's Med Coli, Tokyo,Japan.

Objective: We studied the expression of nitric oxide synthase(NOS) todetermine the involvement of nitric oxide(NO) in the formation of gastricmucosal lesions induced by WIRS.Subjectives: Male Wistar rats weresubjected to water-immersion-restraint stress (WIRS) (0,5,30,60.180,360min. n=5 per group). NOx (griess method), NOS (iNOS, nNOS, eNOS)mRNA expression (RT-PCR) and the ulcer index were determined on theresected stomach. In addition.similar variables were measured after the ratshad been given L-arginine(lOOmglkg) and L-NAME(lOOmglkg) beforeWIRS, Results: (See Table) Discussion: No expression of iNOS wasnoted. In the L-arginine group,increased expression of eNOS was associ­ated with an increase in the NOx concentration.A trend toward decreasedexpression of eNOS was associated with an increase in the ulcer in­dex.These findings suggest that eNOS-induced decrease in mucosal pro­tection afford by NO is involved in the formation of gastric mucosal lesionssubjected to WIRS. Disclosure:This reserch was funded by Institute ofGeriatrics,Tokyo Women' Medical University.Tokyo.Japan.

INOS mRNA expression was notdetected.0' 5' 30' 60' 180' 360'

Control Ulcer index(mm) 0 0 55 73 511 1041NOx(nmollml) 029 0.22 021 024 020 0.23oNOS 1 095 092 096 0.88 0.85eNOS 1 0.98 094 0.82 080 0.64

L·arg Ulcer index(mm) 0 0 0 0 94 105NOx(nmol/ml) 024 023 028 0.32 0.35 0.21nNOS 1 094 0.92 090 090 088eNOS 1 098 160 1.96 1.61 1.52

L·NAME Ulcer index(mm) 0 0 19 40 108 123NOx{nmollml) 0.19 0.25 026 027 022 019nNOS 1 10 092 090 0.89 082eNOS 1 115 090 093 098 105

5697

ESOMEPRAZOLE, THE S-ISOMER OF OMEPRAZOLE, IS OPTI·CALLY STABLE IN HUMANS.Mohammed Hassan-Alin, Mohammad Niazi, Kerstin Rohss, Per-Olof La­gerstrom. AstraZeneca R&D Molndal, Molndal, Sweden.

Introduction: Omeprazole is a racemic mixture of its two optical isomers,S-omeprazole (esomeprazole) and R-omeprazole. Esomeprazole is the firstPPI developed as an optical isomer and has proved to be highly effectivein the treatment of acid related diseases. The aim of the study was toinvestigate if esomeprazole is optically stable in humans. Methods: In anopen study, eight healthy male volunteers (mean age of 25 years and meanweight of 76 kg) were assigned to receive a single oral dose of 40 mgesomeprazole as a capsule. Blood samples for determination of the twoisomers, esomeprazole and R-omeprazole were taken up to 8 hours post­dose. Chiral normal-phase liquid chromatography and mass spectrometry(LC-MS-MS) was used for the determination of esomeprazole and R­omeprazole in plasma. Results: The degree of inversion based on the ratioof the AUC, between R-omeprazole and esomeprazole was 0.4% as shownin the Table. The geometric mean for Cm ax was 0.02 JLmol/L (95% CI:0.01-0.03) for R-omeprazole and 2.68 JLmollL (95% CI: 1.70 - 4.24) foresomeprazole. The compound was well tolerated. Conclusion: Esomepra-