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secretion was determined (60 minutes) and rats given saline or LPS (0.05-20 mg/kg IP), a model used to mimic organ dysfunction. One hour later, rats were given pentagastrin (PG; lOp.g/kg IV) or saline and acid output collected for another two hours. The lowest dose of LPS shown to inhibit acid secretion and not cause gastric injury was also used to assess its effects on H/K-ATPaseexpression.Data were analyzedusing ANOVA(n - 5/group). Results: As shown in the figure below, LPS dose dependentlyinhibited basal and PG stimulated acid secretion. LPS (0.5 mg/kg) increased expression of catalytic a subunit H/K-ATPasemRNA (Northern blot / densitometry) in the absence of PG (1.94 vs. 0.89; p = 0.05) comparedto saline. In the presenceof PG, LPS did not have this effect (0.80 vs. 0.81; p = ns). Western blot analysisdid not show any difference in a subunit immunoraactivity (not shown}. However, confocal microscopy demonstrated that PG increased staining for H/K-ATPasesubunits in the parietal cell secretory membraneswhen compared to controls whereas in all LPS treated rats, H/K-ATPasesubunits were localized to the tubulovesicular elements without insertion into the membrane. Conclusion: These data suggest that gastric colonization during sepsis is due to inhibition of acid secretion by LPS inhibiting internalization of the H/K-ATPase subunits into the secretory membrane rather than by down regulation of transcriptional or translational events.

834 Gastric Acid In The Cardia Escapes Buffering By Food And Remains Highly Acidic After Meals Jonathan Fletcher, Angela A. Wirz, Kenneth E L McColl, Kenneth McEIroy, Univ of Glasgow, Glasgow United Kingdom BACKGROUND:Gastroesophagealreflux (GE)typically occurs after meals. Previouslywe have shown that postprandial retluxate is often more acidic than the contents of the body of the stomach, This suggested regional variation in intragsstric pH after a meal, with an area of high acidity in the proximal stomach. AIMS AND METHODS:This study aimed to directly measure the pH profile of the proximal stomach. Ten healthy subjects underwent dual pH electrode pull through studies under fasting and postprandial conditions. The pH catheter was positioned in the stomach and then withdrawn by lcm increments. The pH at each catheter position and the distanceof the step-up to oesophagealpH. RESULTS:Underfasting conditions the pull through studies revealeda stable intragastric pH throughout the stomach, median pH 1.5 (range 0.7-1.9). After a meal, the extent of food related buffering varied throughout the stomach with the cardia remaining highly acidic comparedto the body of the stomach, median pH 1.4 (range 0.9-5.0) vs median pH 4.6 (range 2.0-6.7) (p<0.01) (Figure). CONCLUSIONS: The cardia escapes the buffering offset of meals. The presence of this unbuffered pocket of acid immediately below the GE junction is likely to be important in the pathogenesisof GERD.

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Doxepin, A Tricyclic Antidepressant, Centrally inhibits Gastric Acid Secretion, Acting On The Neurons Probably Located In The Medulla Oblongata in Conscious Dogs. Tomohiko Shimatani, Masaki Inoue, Masazumi Okajima, Katsutumi Kawahori, Hiroshima Univ Sch of Medicine, Hiroshima Japan; Kazumoto Fujii, Japanese Red Cross Hiroshima Coil of Nursing, Hiroshima Japan BACKGROUND:Some tricyclic drugs are used clinically to treat anxiety and depression,and known to have central gastric antisecretory effects. Doxepin hydrochloride also inhibits acid secretion and its use in treating patients with peptic ulcer diseasewas suggested, but since the discovery of Helicobacterpylori and the development of proton pump inhibitors, it has been completely forgotten. The anatomical sites and mechanisms of action appearedto be centrally mediated but were not clear. To clarify them, the following experiments were performed. METHODS:12 healthy mongrel dogs of either sex weighing 12.6-14.0kg were used in these experiments Under pentobarbital sodium anesthesia, each was furnished with a simple gastric fistula. A truncal vagotomy was also performed on 2 of these dogs at the level of the abdominal esophagus. The effects of Doxepin on gastric acid secretion induced by various agents were investigated in a conscious state without restraint. Upon 7 of them, under pentobarbital sodium anesthesia with a respirator, the experiments were performed after surgical transection of the pontomedullary transition. RESULT: In a conscious state Doxepin dose-dependentlyinhibited gastric acid secretion stimulated by 2-deoxy-D-glucose (2-DG) (50mg/kg, i.v.), and at a dose of 10mg/kg (i. g.) Doxepin completely inhibited it. On the other hand, Doxepin did not inhibit insulin (0.5U/kg, i.v.)-induced centrally mediated gastric acid secretion. Doxepin also did not significantly inhibit pentagastrin (3/~]/kg, s.c.)or betazolehydrochloride (lmg/kg, s.c.) (histamine receptor agonist)-inducad peripheralgastric acid secretion in truncal vagotomizeddogs. Under anesthesia,evenafter the intercollicular transection, 2-DG-induced gastric acid secretion was still observed and Doxepin inhibited it, but insulin-induced secretion was not observed. CONCLUSIONS:In dogs Ooxepin centrally inhibits only 2-DG-induced gastric acid secretion in a conscious state or after transection of the brain-stem. These results suggest that neurons sensitive to functional cytoglucopeniaare located in the medulla oblongata, probably in the nuclei of the solitary tract, and Doxepin inhibits these neurons. 837 Percent Time, Integrated Intragastric Acidity Or Acidity Index? Radu I. Tutuian, Philip O. Kalz, Shuwen Xue, Donald O. Castell,Graduate Hosp, Philadelphia, PA Background: Percenttime intragastric pH <4 and pH <3 are major parametersin the analysis of the efficiency of acid-supprassivetherapies. Percent time intragastric pH <4 is easy to calculate but it does not differentiate how low the pH aetually is (i.e. just below 4,0 or 1.0). Recent studies recommend using integratedintragastric acidity (calculated using the anti-log of measuredpH values) as a more refined method in assessingintragastric acid control. Aim: Assess if a new defined parameter (acidity index) can overcome the limitations of percent time pH <4 and intragastric acidity. Methods: Acidity index (AI) was defined as [% time pH 3.1 - 4.0] + [% time pH 2.1 - 3.0]x10 + [% time pH 1.1 - 2.0]x100 + [% time pH 0.01.0]x1000 for any given period of time. Total percent time intragastric pH < 4 and <3, 24h integrated intragastric acidity and acidity index for total 24-h were calculated using 203 intragastric pH studies from 72 healthy volunteers taking once daily PPI. Correlationbetween percent time intragastric pH <4 and 24-h integrated intragastric acidity as well as between acidity index for 24-h and 24-h integrated intgastric acidity were calculated. Results: 24-h integrated intragastric acidity ranged from 0.06 to 357.12 (mean _+ SD = 46.42 -+ 49.02). Percent time pH < 4 ranged from 2.1% to 99.7% (mean _+ SD = 59.8% -+ 22.5%). Acidity index ranged from 330 to 988419 (mean + SD = 248715 -+ 228426). The correlation coefficient between acidity index over 24-h and the 24-h integrated intragastric acidity (r = 0.93) was superior to the correlation between total 24-h percent time intragastric pH < 4 and 24-h integrated intragastric acidity (r = 0.65). Conclusion: Acidity index is easy to calculate and allows a more accurate assessment of the intragastric pH and should be considered in assessing intragastric pH control.

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Demonstration of a Busolateral NHE3 Exchanger in Isolated Rat Gastric Glands Klaus Radebold,Mark B. Hansen,John P. Geibel, Yale Univ, New Haven, CT

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Background. Previous studies in rat gastric parietal cells have shown an active basolateral sodium-hydrogen exchangerprotein (NHE). Aims. To determine if there were more than one functional NHE isoform at the basolateralmembrane of the gland. Methods. Individual hand dissectedgastric glandswere isolatedand loadedwith the pH sensitivedye BCECF.Intracellular pH (pHi) changes were monitored with a high speed imaging system during modifications of extracellularion concentrations.Glandswere mounted on a thermostatically controlled perfusiGn chamber and maintainedat 37°C during the course of the study. To investigatethe Na+H+ exchanger all studies were carried out in the absence of HC03. After the acid load intracellular pH was continuously monitored in glands superfusedeither with standardRinger, or low Na+ Ringer. Results. Re-addition of Na÷ following the acid load resulted in a rapid reversible alkalinization of the cells. However, addition of the NHE3 specific inhibitor Ethyl Isopropal Amiloride (2 vM) inhibited 95% of the recovery from the acid load. When coupled to studieswith cimetidine (100/~M), a known inhibitor of NHE1and NHE2at this concentration, only NHE3 appearsactive on the basolateral membrane of the rat gastric gland. Conclusion. We conclude that the rat gastric gland has a functional NHE3 protein on the basolateral membrane. This protein seems to be capable of maintaining intracellular pH follwing an acid load.

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o 838 Intravenous Pantoprazole Rapidly Achieves pH>4.0 in ICU Patients Without the Development of Tolerance. L Somberg, Medical Coil of Wisconsin, Milwaukee, WI; R Kadstadt, K Gallagher, WyethAyerst PharmaceuUcals,Inc, Philadelphia,PA; J McDevitt, Medex Clin Trial Service, Inc, Philadelphia, PA; J Graepel,Wyeth-Ayerat Pharmaceuticals,Inc, Philadelphia,PA; V Paoletti, Medex Clin Trial Service, Inc, Philadelphia,PA; Icu PantoprazoleStudy Group A muiticenter study was conducted comparing four dosing regimens of IV pantoprazole(P), a proton pump inhibitor, and the standardapprovedregimenof continuous infusion cimetidine (C) to evaluatethe intragastric pH in iCU patients.Percentof time pH >4.0 has beenassociated with a lower incidence of UGI Bleedingin this population, suggesting that time to reach and

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