Selective blockage of cell membrane K conductance by an antisecretory agent in guinea-pig gallbladder epithelium

Abstract

Loperamide inhibits PGE₁-induced electrogenic HCO₃ secretion in guinea-pig gallbladder. Underlying changes in epithelial cell membrane properties were investgated using intracellular microelectrode techniques in vitro. In the absence of PGE₁, mucosal loperamide (10⁻⁴ mol/l) reversibly depolarized both cell membranes by ∼ 6 mV. The apparent ratio of membrane resistances (R _a/R _b) remained unchanged and so did voltage responses to luminal Cl removal and Na reduction. The depolarizing response to elevation of luminal K concentration from 5 to 76 mmol/l was decreased from 13 to 8 mV. In the presence of 1 PGE₁, the apical membrane is mainly permeable to Cl and HCO₃. Under these conditions, loperamide reduced membrane potentials by ∼ 10 mV,R _a/R _b remaining constant at ∼ 0.4. Effects on voltage responses to changes in luminal Na or K concentration were unchanged. Responses to luminal Cl removal (transient depolarization) were greatly enhanced (from 22 to 42 mV) as predictable from the fall in K permeability that hinders Cl efflux from cell into lumen. Less marked but significant effects were obtained with 10⁻⁵ mol/l (mucosal side) and serosal loperamide (10⁻⁴ mol/l). We suggest that loperamide inhibits electrogenic HCO₃ secretion by reducing apical membrane K permeability. The resulting depolarization diminishes the driving force for conductive anion efflux from cell into lumen. This conclusion is supported by the ability of luminal K elevation to mimick loperamide inhibition of the secretory flux of HCO₃ (pH-stat experiments).