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1 CURE: Digestive Diseases Research Center, Los Angeles, CA, USA; Brentwood Biomedical Research Institute, Los Angeles, CA, USA
2 Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA
3 Brentwood Biomedical Research Institute, Los Angeles, CA, USA
4 Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA; CURE: Digestive Diseases Research Center, Los Angeles, CA, USA; Department of Medicine, School of Medicine, University of Californina, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: jake{at}ucla.edu.
Background: Luminal exposure to concentrated acid, the most accepted physiologic stimulus for duodenal bicarbonate secretion, cannot be used with in vitro preparations due to potential tissue damage. We thus examined if exposure to prostaglandin E2 (PGE2), a well characterized physiologic duodenal secretagogue, could mimic the effects of acid perfusion. Methods: Duodenal bicarbonate secretion was measured in C57/BL mice by pH-stat/back-titration and measurement of total dissolved CO2 content ([CO2]t). The anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), the carbonic anhydrase inhibitor methazolamide, and the nonselective cyclooxygenase inhibitor indomethacin were used to inhibit separate components of the HCO3- secretory pathway. Results: Baseline duodenal bicarbonate secretion was not altered by exposure to methazolamide (0.1mM), but slightly reduced by DIDS (0.5mM). Duodenal bicarbonate secretion and [CO2]t increased after acid and PGE2 exposure. DIDS (0.5mM) and NPPB (0.2mM) abolished acid-induced duodenal bicarbonate secretion increase. Methazolamide (0.1mM) and DIDS inhibited acid-induced [CO2]t increase. DIDS, NPPB or methazolamide little effect on duodenal bicarbonate secretion in response to high concentration PGE2 (100µg/ml). Low concentration PGE2 (1µg/ml) increased duodenal bicarbonate secretion that was inhibited by DIDS, NPPB and methazolamide. Pretreatment with indomethacin (5mg/kg) inhibited duodenal bicarbonate secretion induced by acid exposure, but not by PGE2. Conclusion: High-dose PGE2 substantially increases duodenal bicarbonate secretion by a mechanism that appears to be different than the secretory response to luminal acid perfusion. The secretory response to low-dose PGE2, at least in terms of inhibitor profile, closely resembles secretion in response to perfusion of physiological acid concentrations, and may be a useful stimulus for in vitro study of duodenal bicarbonate secretion in isolated mouse duodenum.
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