Defective colonic Na+ and Cl− absorption is a feature of active ulcerative colitis (UC), but little is known about changes in colonic K+ transport. We therefore investigated colonic K+ transport in a rat model of dextran sulfate-induced colitis. Colitis was induced in rat distal colon using 5% dextran sulfate sodium (DSS). Short-circuit current ( Isc, indicating electrogenic ion transport) and 86Rb (K+ surrogate) fluxes were measured in colonic mucosa mounted in Ussing chambers under voltage-clamp conditions in the presence of mucosal orthovanadate (a P-type ATPase inhibitor). Serum aldosterone was measured by immunoassay. Control animals exhibited zero net K+ flux. By contrast, DSS-treated animals exhibited active K+ secretion, which was inhibited by 98, 76, and 22% by Ba2+ (nonspecific K+ channel blocker), iberiotoxin (IbTX; BK channel blocker), and TRAM-34 (IK channel blocker), respectively. Apical BK channel α-subunit mRNA abundance and protein expression, and serum aldosterone levels in DSS-treated animals, were enhanced 6-, 3-, and 6-fold respectively, compared with controls. Increasing intracellular Ca2+ with carbachol (CCH), or intracellular cAMP with forskolin (FSK), stimulated both active Cl− secretion and active K+ secretion in controls but had no or little effect in DSS-treated animals. In DSS-induced colitis, active K+ secretion involves upregulation of apical BK channel expression, which may be aldosterone-dependent, whereas Cl− secretion is diminished. Since similar ion transport abnormalities occur in patients with UC, diarrhea in this disease may reflect increased colonic K+ secretion (rather than increased Cl− secretion), as well as defective Na+ and Cl− absorption.
Two Studies on Reversal of Opioid-induced Respiratory Depression by BK-channel Blocker GAL021 in Human Volunteers
