Calcitonin gene-related peptide (CGRP) added to the internal fluid bathing the isolated skin of Rana esculenta strongly stimulates the active sodium absorption. This action is dose-dependent, the dose eliciting the maximal effect being 2 . 10(-7) M; alpha and beta CGRP exhibit the same potency. The CGRP action on sodium transport is mainly due to its interaction with CGRP1 receptors, since it is inhibited by CGRP8-37, its specific antagonist. The second messengers probably involved in the action of CGRP are cAMP and Ca+2, since this action is reduced by SQ22536 and W7, which are inhibitors of adenyl cyclase and calmodulin respectively. On the contrary, inhibitors of protein kinase C (1-O-hexadecyl-2-O-methyl-sn-glycerol) and nitric oxide synthase (L-NAME) do not modify the action on sodium transport. ETYA, an inhibitor of all the metabolic pathways of arachidonic acid, decreases the CGRP action by 38%. In order to search for the arachidonic acid metabolites involved in the CGRP action, the effect of the following inhibitors was tested: aspirin and naproxen (for cyclooxygenases), NDGA (for cyclooxygenases), NDGA (for lipoxygenases) clotrimazole (for epoxygenases). None of these substances is able to inhibit the CGRP action on sodium transport. Moreover, adding arachidonic acid inhibits the CGRP action, but this effect was also obtained by another unsaturated fatty acid, oleic acid. Since unsaturated fatty acids are able to inhibit the protein kinase A, these results indirectly support the role of cAMP as a second messenger of the CGRP action on sodium transport.