Gossypol induces chloride secretion in rat proximal colon

The effect of gossypol on electrolyte transport was investigated in rat colon mounted in Ussing chambers. The addition of gossypol to the mucosal or serosal side led to an increase in mucus secretion, which we did not quantify. Mucosally or serosally added gossypol also induced a rise in short circuit current (I(sc)) and tissue conductance (G(t)). Part of the mucosally added gossypol seemed to be bound to the mucus because the effects on I(sc) and G(t) were smaller when gossypol was added to the mucosal side. Serosally added gossypol had an effect on I(sc) at a concentration of 10 micromol l(-1). Mucus secretion was reduced in low Ca(2+) buffer. The increase in I(sc) was diminished by blockers of Cl- channels, K+ channels, of the Na+/K+ ATPase and of the Na+/K+/2 Cl- cotransporter. Measurements of unidirectional ion fluxes showed that gossypol added to the mucosal side had no effect on net Na+ transport, but increased Cl- secretion. The effect of mucosally added gossypol was significantly reduced by the use of low Cl- buffers and abolished when the buffer was additionally depleted of HCO(3)(-). Calmodulin antagonists inhibited the effect on secretion. These findings indicate that gossypol induces chloride secretion via a calmodulin-dependent mechanism. High concentrations of gossypol induced a strong increase in G(t) that could be blocked by W7, a blocker of calmodulin-dependent myosin light chain kinase. This indicates that the rise in G(t) is not due to an unspecific toxic effect, but instead, to specific opening of tight junctions.