CADMIUM DISRUPTS THE SIGNAL-TRANSDUCTION PATHWAY OF BOTH INHIBITORY AND STIMULATORY RECEPTORS REGULATING CHLORIDE SECRETION IN THE SHARK RECTAL GLAND

The heavy metal cadmium causes nephrotoxicity and alters the transport function of epithelial cells. In the shark rectal gland, chloride sec retion is regulated by secretagogues and inhibitors acting through rec eptors coupled to G proteins and the cyclic AMP-protein kinase A pathw ay. We examined the effects of cadmium on the response to the inhibito ry peptide somatostatin (SRIF), and to the stimulatory secretagogues f orskolin and vasoactive intestinal peptide (VIP). In control experimen ts, SRIF (100 nM) entirely inhibited the chloride secretory response t o 10 mu M forskolin (maximum chloride secretion with forskolin 1984 +/ - 176 mu Eq/h/g; with forskolin + SRIF 466 +/- 93 mu Eq/h/g, P < 0.001 ). Cadmium (25 mu M) entirely reversed the inhibitory response to SRIF (chloride secretion 2143 +/- 222 mu Eq/h/g) and caused an overshoot ( 2917 +/- 293 mu Eq/h/g) that exceeded the response to forskolin (P < 0 .01). Cadmium also enhanced forskolin-stimulated chloride secretion (2 628 +/- 418 vs. 1673 +/- 340 mu Eq/h/g, P < 0.02) and reversed the dec lining phase of the forskolin response. Cadmium had a concentration-de pendent, biphasic effect on the response to VIP. Cd (10-100 mu M) incr eased both chloride secretion and tissue cyclic AMP content, whereas h igher concentrations (1 mM) inhibited chloride secretion and cyclic AM P accumulation. Our findings provide evidence that Cd disrupts the sig nal transduction pathways of both inhibitory receptors and secretagogu es regulating cAMP mediated transport in an intact epithelia. The resu lts are consistent with direct effects of cadmium on adenylate cyclase and/or phosphodiesterase activity in this marine epithelial model. (C ) 1997 Wiley-Liss, Inc.