title: Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs; 1) are widely recommended for several acute and chronic conditions. For example, both indomethacin and aspirin are taken for pain relief. Aspirin is also used for prevention of myocardial infarction, and indomethacin can be administered orally or as a suppository for patients with rheumatoid disease and other chronic inflammatory states. However, use of NSAIDs can cause damage to the mucosal barrier surrounding the gastrointestinal (GI) tract, increasing the risk of ulcer formation. While microencapsulation of NSAIDs has been shown to reduce upper GI injury, sustained release in the lower GI tract and colon may cause epithelial erosion due to increased acidification. The use of suppositories has also been linked to rectal and lower GI bleeding. In this study, we investigated the role of NSAIDs aspirin and indomethacin on Na⁺/H⁺ exchanger (NHE) activity in rat colonic crypts. By comparing average rates of pH recovery between control and NSAID perfusion runs, we were able to determine that both aspirin and indomethacin increase hydrogen extrusion into the colonic lumen. Through treatment with 5-ethylisopropyl amiloride (EIPA), amiloride, and zoniporide dihydrochloride, we further demonstrated that indomethacin specifically enhances proton excretion through regulation of apical NHE-3 and NHE-2 and to a lesser extent on basolateral NHE-1 and NHE-4. Our results suggest that clinical exposure to NSAIDs may affect colonic tissue at the site of selected NHE isoforms, resulting in modulation of transport and barrier function.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Aliya C
authors.initials: AC
authors.lastname: Roginiel
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kohut
authors.forename: Sumanpreet
authors.initials: S
authors.lastname: Kaur
authors.forename: Ahmad M A
authors.initials: AM
authors.lastname: Saleh
authors.forename: Theresa
authors.initials: T
authors.lastname: Weber
authors.forename: Peter
authors.initials: P
authors.lastname: Geibel
authors.forename: Harmeet
authors.initials: H
authors.lastname: Singh
authors.forename: John P
authors.initials: JP
authors.lastname: Geibel
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D062686:Epithelial Sodium Channel Blockers; D006146:Guanidines; D011720:Pyrazoles; C000613385:SLC9A3 protein, human; C513110:Slc9a2 protein, rat; C000613387:Slc9a3 protein, rat; C081518:Slc9a4 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D000584:Amiloride; C424422:zoniporide; D001241:Aspirin; C039614:ethylisopropylamiloride; D007213:Indomethacin
keywords: EIPA; GI tract; amiloride; aspirin; colon; indomethacin; inflammation; intestine; ion transport; pH; zoniporide