Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts

TY - JOUR

T1 - Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts

AU - Roginiel, Aliya C

AU - Kohut, Daniel L

AU - Kaur, Sumanpreet

AU - Saleh, Ahmad M A

AU - Weber, Theresa

AU - Geibel, Peter

AU - Singh, Harmeet

AU - Geibel, John P

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Amiloride/analogs & derivatives

KW - Animals

KW - Anti-Inflammatory Agents, Non-Steroidal/pharmacology

KW - Aspirin/pharmacology

KW - Colon/drug effects

KW - Epithelial Sodium Channel Blockers/pharmacology

KW - Gene Expression Regulation/drug effects

KW - Guanidines/pharmacology

KW - Humans

KW - Hydrogen-Ion Concentration

KW - Indomethacin/pharmacology

KW - Ion Transport/drug effects

KW - Male

KW - Pyrazoles/pharmacology

KW - Rats

KW - Rats, Sprague-Dawley

KW - Sodium-Hydrogen Exchanger 3

KW - Sodium-Hydrogen Exchangers/agonists

U2 - 10.1152/ajpcell.00303.2012

DO - 10.1152/ajpcell.00303.2012

M3 - SCORING: Journal article

C2 - 23739181

VL - 305

SP - C512-8

JO - AM J PHYSIOL-CELL PH

JF - AM J PHYSIOL-CELL PH

SN - 0363-6143

IS - 5

ER -