Stereospecific inhibition by ozolinone of stimulated chloride secretion in rabbit colon descendens

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Abstract
The effects of the diuretic drug ozolinone on electrogenic Cl− secretion by rabbit colonic mucosa were investigated in vitro. Electrical properties and unidirectional Cl− fluxes were measured in stripped preparations mounted in Ussing-type chambers. After abolition of electrogenic Na+ absorption by amiloride (10−4 mol/l) on the mucosal side electrogenic Cl− secretion was induced by addition of PGE1 (10−6mol/l, serosal side) and theophylline (10−2mol/l, both sides). Under these conditions, the monitored short-circuit current (Isc) equals the amount of Cl− secreted as evidenced by determination of unidirectional Cl− fluxes. After establishing a stable Cl− secretion its sensitivity to the enantiomers of the diuretic was studied. Only levorotatory (-)-ozolinone, but not the dextrorotatory (+)form, inhibited Cl− secretion on serosal application. This effect was fully accounted for by a reduction in the serosal-to-mucosal Cl− fluxes (J sm Cl ). It was readily reversible and concentration-dependent with a K i value of 6×10−4mol/l, but absent when the drug was added to the mucosal side. The results are in agreement with the hypothesis that loop diuretics inhibit a coupled NaCl entry mechanism across the baso-lateral membrane into colonic epithelial cells. This mechanism is though to account for Cl− influx into the cells.

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