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.

Gene Expression in the Human Endolymphatic Sac

“…The present study confirms this finding, as the SLC9a2 gene was found highly expressed compared to dura. The blocking effect of amiloride on this particular transporter is well known, but lately it has also been demonstrated that several non-steroid anti-inflammatory drugs (NSAIDs) also interact and block the transporter (23), which may in fact account for the well-known side effects of many NSAIDs, including tinnitus, dizziness, and imbalance. Accordingly, the present data supports a cautious approach when administering both amiloride and NSAIDs in patients with Ménière's disease.…”

Acute Effects of Vitamin C Exposure On Colonic Crypts: Direct Modulation of pH Regulation

“…The colon was then removed and flushed with 4°C cold HEPES Ringer solution (See Table 1) to remove the residual fecal material from the interior of the colon as previously described [20]. Briefly, we cut the clean distal colon into two longitudinal strips [21, 22]. The two strips were then immersed into a digestion solution that was composed of a low Calcium High EDTA/HEPES buffer.…”

“…We then transfer a 200 µL aliquot of the crypts HEPES solution to the chamber, then incubated the crypts with a 1 µL of BCECF/AM dye (Santa Cruz Biotechnology) a pH sensitive dye as previously described [22, 24]. …”

“…The BCECF loaded crypts were excited at 490 and 440 nm±20nm respectively while collecting the emission at 530 nm±20nm every 15s. The pH was calculated using the High-K/Nigericin calibration technique [22] previously used in our laboratory.…”

Effects of Indomethacin on Intracellular pH and Na^+/H^+ Exchanger in the Human Monocytes

“…Indomethacin, a highly potent nonsteroidal anti-inflammatory drug with nonselective inhibition on cyclooxygenases (5) is known to possess both prominent anti-inflammatory and analgesic-antipyretic properties (12). The clinical use of indomethacin has been effectively used in various clinic conditions, such as several acute and chronic pains (40), rheumatoid arthritis (45) and ocular inflammation (19). Apart from the potent inhibition on cyclooxygenases, the anti-inflammatory and analgesic effects of indomethacin is also achieved through a variety of mechanisms, including regulation of NHE (40) and Cl -/HCO 3 ion transporter (48).…”