We have previously demonstrated that formate and oxalate stimulate transcellular Cl- absorption (JCl) in the rat proximal tubule by a mechanism involving DIDS-sensitive anion exchange across the luminal membrane and diphenylamine-2-carboxylate (DPC)-sensitive Cl- channels in the basolateral membrane. Recent evidence indicates cAMP activation of Cl- channels in apical and basolateral membranes of proximal tubule cells. We therefore tested the effect of cAMP on Cl- and fluid transport in rat proximal tubule studied by luminal and capillary microperfusion in situ. The luminal perfusate contained 5 mM HCO3- and 145 mM Cl-, and the capillary perfusate contained 25 mM HCO3- and 110 mM Cl-, simulating conditions in the late proximal tubule. Addition of 0.5 mM dibutyryl cAMP markedly stimulated fluid absorption (Jv) and JCl. Similar effects resulted from addition of forskolin (10 microM) to stimulate cAMP production. The increments in Jv and JCl due to dibutyryl cAMP were abolished when the Cl- channel blocker DPC (200 microM) was added to the capillary perfusate but not when it was added to the lumen. The increments in Jv and JCl due to dibutyryl cAMP were unaffected by luminal DIDS (100 microM), which abolishes the increments in Jv and JCl induced by addition of oxalate. In contrast, the increments in Jv and JCl due to dibutyryl cAMP were abolished by luminal 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB; 10 microM), another Cl- channel blocker. Luminal NPPB had no effect on baseline Jv and JCl nor on the increments in Jv and JCl induced by addition of oxalate.(ABSTRACT TRUNCATED AT 250 WORDS)