Interaction of cadmium with atrial natriuretic peptide receptors: implications for toxicity

Atrial natriuretic peptide (ANP) is a diuretic and vascular smooth muscle relaxant which plays a pivotal role in cardiovascular regulation. Since cadmium (Cd) produces cardiovascular toxicity and alters ANP levels in atria and hypothalamus, its effect on ANP receptors were studied in rats and in PC12 cells exposed to Cd. Male rats were injected with CdCl2 (0.01, 0.1, 0.5 or 1.0 mg/kg, i.p.) twice a day for 7 days and then maintained for a period of 30 days. On experimental day 37 ANP receptor binding in the adrenal cortex, aorta and kidney cortex was studied by saturation isotherm analysis. In Cd-treated animals a non-dose related decrease in receptor affinity and density was observed in the kidney and aorta with the aortic ANP receptors being the most sensitive. Cellular regulation of the receptor was studied in PC12 cells, a cell line that expresses functional ANP receptors. Incubation of PC12 cells with Cd reduced both the affinity of the receptor for ANP and decreased the number of binding sites on the cell plasma membrane. The ratio of ligand-receptor complex internalized in the cell to ligand bound to the plasma membrane was significantly decreased following Cd pretreatment (500 microM). A significant decrease in the internalization rate of [125I]ANP was observed in cells incubated concurrently with Cd and ligand. In photoaffinity labelling studies with [125I]ANP, binding of ANP to B and C receptors subtypes was decreased following treatment of either intact cells or plasma membranes with Cd. It was concluded that Cd produces significant alterations in the ANP receptor, both in in vitro and in vivo models and it is proposed these effects play a role in the cardiovascular toxicity of this heavy metal.