We have previously found that arginine vasopressin (AVP) acts not only from the basolateral side but also from the luminal side of the rabbit cortical collecting duct (CCD). In the present study, we examined whether prostaglandin E(2) (PGE(2)), another classic and potent modulator of the collecting duct functions, exerts luminal actions in the rabbit CCD perfused in vitro. Although luminal prostaglandin I-2 was inert, luminal PGE(2) (>1 nM) induced transient hyperpolarization of transepithelial voltage followed by sustained depolarization in a dose-dependent manner. This action was preserved in the presence of basolateral PGE(2), luminal AVP, or luminal BaCl2, but abolished by basolateral ouabain or luminal amiloride. Furthermore, unlike luminal AVP, luminal PGE(2) suppressed Na transport and increased osmotic water permeability. The present study suggests that PGE(2), similar to AVP but in a different fashion, modulates transepithelial transports from both luminal and basolateral sites in the CCD in vivo.