The C-type natriuretic (CNP) peptide signals through the type B natriuretic peptide receptor (NPR-B) in vascular smooth muscle cells to activate the particulate guanylyl cyclase activity intrinsic to that receptor and raise cellular cyclic GMP levels. In the present study, we demonstrate that CNP downregulates the expression of this receptor leading to a reduction in NPR-B activity. Pretreatment of rat aortic smooth muscle cells with CNP reduces NPR-B activity, NPR-B protein levels, NPR2 (NPR-B gene) mRNA levels and NPR2 promoter activity. The decrease in NPR2 promoter activity is dependent upon DNA sequence present between -441 and -134 relative to the transcription start site. The reduction in NPR2 gene expression appears to operate through generation of cyclic GMP. 8-bromo cyclic GMP, a membrane-permeable cyclic GMP analog, reduced NPR2 mRNA levels and NPR2 promoter activity. Atrial natriuretic peptide which signals through the type A natriuretic peptide receptor (NPR-A) to increase cyclic GMP levels in these cells, also reduced NPR-B mRNA levels and inhibited NPR-B promoter activity; however, this inhibition was not additive with that produced by CNP, implying that the two ligands traffic over a common signal transduction pathway. This report provides the first documentation that CNP is capable of auto-regulating the expression of its cognate receptor.