The heavy metal cadmium causes nephrotoxicity and alters the transport function of epithelial cells. In the shark rectal gland, chloride secretion is regulated by secretagogues and inhibitors acting through receptors coupled to G proteins and the cyclic AMP-protein kinase A pathway. We examined the effects of cadmium on the response to the inhibitory peptide somatostatin (SRIF), and to the stimulatory secretagogues forskolin and vasoactive intestinal peptide (VIP). In control experiments, SRIF (100 nM) entirely inhibited the chloride secretory response to 10 μM forskolin (maximum chloride secretion with forskolin 1984 ± 176 μEq/h/g; with forskolin + SRIF 466 ± 93 μEq/h/g, P < 0.001). Cadmium (25 μM) entirely reversed the inhibitory response to SRIF (chloride secretion 2143 ± 222 μEq/h/g) and caused an overshoot (2917 ± 293 μEq/h/g) that exceeded the response to forskolin (P < 0.01). Cadmium also enhanced forskolin-stimulated chloride secretion (2628 ± 418 vs. 1673 ± 340 μEq/h/g, P < 0.02) and reversed the declining phase of the forskolin response. Cadmium had a concentration-dependent, biphasic effect on the response to VIP. Cd (10-100 μM) increased both chloride secretion and tissue cyclic AMP content, whereas higher concentrations (1 mM) inhibited chloride secretion and cyclic AMP accumulation. Our findings provide evidence that Cd disrupts the signal transduction pathways of both inhibitory receptors and secretagogues regulating cAMP mediated transport in an intact epithelia. The results are consistent with direct effects of cadmium on adenylate cyclase and/or phosphodiesterase activity in this marine epithelial model.