The lipophilic nitric oxide-liberating drug, 1,2,3,4-oxatriazolium,5-amino-3-(3,4-dichlorophenyl)-chloride (GEA 3162), concentration-dependently induced a Cl(-) secretion in rat colon. At a low concentration (5 x 10(-5) M), the action was Ca(2+)-dependent, whereas at a high concentration (5 x 10(-4) M), the response was independent from extracellular Ca(2+). Fura-2 experiments at isolated colonic crypts revealed that GEA 3162 induced an increase of the cytoplasmic Ca(2+) concentration due to an influx of extracellular Ca(2+), probably mediated by an activation of a nonselective cation conductance as demonstrated by whole-cell patch-clamp studies. After depolarization of the basolateral membrane, GEA 3162 (5 x 10(-4) M) stimulated a current, which was suppressed by glibenclamide but was resistant against blockade of protein kinases by staurosporine, suggesting an activation of apical Cl(-) channels directly by the nitric oxide (NO) donor. After permeabilizing the apical membrane with the ionophore, nystatin, GEA 3162 (5 x 10(-4) M) activated basolateral K(+) conductances and the Na(+)-K(+)-ATPase. Thus, the lipophilic NO donor GEA 3162 stimulates a Cl(-) secretion in a Ca(2+)-dependent and -independent manner.