THE ANTIFUNGAL ANTIBIOTIC, CLOTRIMAZOLE, INHIBITS CHLORIDE SECRETION BY HUMAN INTESTINAL T84 CELLS VIA BLOCKADE OF DISTINCT BASOLATERAL K- DEMONSTRATION OF EFFICACY IN INTACT RABBIT COLON AND IN AN IN-VIVO MOUSE MODEL OF CHOLERA( CONDUCTANCES )

The antifungal antibiotic clotrimazole (CLT) blocks directly and with high potency the Ca2+-activated K+ channels of human erythrocytes, ery throleukemia cells, and ferret vascular smooth muscle cells, We recent ly reported that CLT inhibits Cl- secretion in human intestinal T84 ce lls, likely by affecting K+ transport (Rufo, P.A., L, Jiang, S.J. Moe, C. Brugnara, S.L. Alper, and W.I. Lencer, 1996, J. Clin. Invest. 98:2 066-2075). To determine if CLT had direct effects on K+ conductances i n T84 cells, we selectively permeabilized apical membranes of confluen t T84 cell monolayers using the ionophore amphotericin B. This techniq ue permits direct measurement of basolateral K+ transport, We found th at CLT and a stable des-imidazolyl derivative inhibited directly two p harmacologically distinct basolateral membrane K+ conductances, but ha d no effect on apical membrane Cl- conductances. The effects of CLT on Cl- secretion were also examined in intact tissue. CLT inhibited fors kolin-induced Cl- secretion in rabbit colonic mucosal sheets mounted i n Ussing chambers by 91%. CLT also inhibited cholera toxin-induced int estinal Cl- secretion in intact mice by 94%, These data provide direct evidence that CLT blocks Cl- secretion in intestinal T84 cells by inh ibition of basolateral K+ conductances, and show that CLT inhibits sal t and water secretion from intact tissue in vitro and in vivo. The res ults further support the suggestion that CLT and its metabolites may s how clinical efficacy in the treatment of secretory diarrheas of diver se etiologies.