Free cytosolic Ca2+ [( Ca2+]i) has been implicated as a second messenger mediating the ion transport effects of carbachol, histamine, taurodeoxycholate, ionomycin, and 4-bromo-A23187 (4-BrA23187) in T84-cells. In this study, we correlated short-circuit current (Isc, reflective of Cl- secretion) and [Ca2+]i responses in T84-cell monolayers stimulated by these agents to evaluate the role of [Ca2+]i in Cl- secretory responses. Time-course studies showed that the duration of [Ca2+]i and Isc responses did not correlate with one another. Isc responses were more prolonged than [Ca2+]i responses with carbachol and histamine (both derived [Ca2+]i partly from intracellular sources), less prolonged than [Ca2+]i with taurodeoxycholate, and continued to increase after [Ca2+]i stabilized with ionomycin and 4-BrA23187. Isc and [Ca2+]i responses to histamine and carbachol were additive. A comparison of the magnitude of [Ca2+]i and Isc responses in cells stimulated by different agonists showed that the change in [Ca2+]i accompanying equivalent Isc responses varied greatly, suggesting that secretagogues vary in their dependency on [Ca2+]i. These findings suggest the existence of multiple [Ca2+]i-mediated effector mechanisms or the existence of multiple mediators that augment or attenuate the action of [Ca2+]i.