The effect of C-type natriuretic peptide (CNP), a novel member of the natriuretic peptide family, on cyclic GMP (cGMP) generation was studied in primary cultures of mouse astrocytes. CNP stimulated cGMP production by mouse astrocytes in a dose-dependent fashion, with an EC50 of 32 nM and a maximal stimulatory concentration of greater than 1 microM, which induced a rise of cGMP level from a baseline of 1.0 +/- 0.1 pmol/mg of protein to 196.2 +/- 22.0 pmol/mg of protein. Compared with our previously reported atrial and brain natriuretic peptide-induced cGMP responses, CNP had a lower EC50 and was 10-20 times more efficacious in its maximal effect on cGMP stimulation. These data lend support to the concept of a significant role of CNP in neuromodulation/neurotransmission.