It has been shown that atrial natriuretic peptide (ANP) influences proliferation of cardiac cells. To define the possible role of C-type natriuretic peptide (CNP) in cardiac hypertrophy, the influence of CNP on the secretion of ANP was studied with the use of perfused nonbeating atria from monocrotaline-treated rats. Increases in atrial volume caused proportional increases in ANP secretion that were markedly suppressed by CNP (10⁶ M) in nonhypertrophied left atria and control right atria but not in hypertrophied right atria. However, increases in atrial volume and mechanically stimulated extracellular fluid (ECF) translocation by CNP were similar to those in the control group. Therefore, the secretion of ANP in terms of ECF translocation was decreased by CNP in nonhypertrophied left and control right atria but not in hypertrophied atria. However, the inhibitory effect of 8-bromo-cGMP on the secretion of ANP was observed in both atria. The cGMP productions from perfused hypertrophied atria and their membranes exposed to CNP were significantly lower than those from nonhypertrophied atria. No significant difference in natriuretic peptide receptor-B transcript was found. Therefore, attenuation of the inhibitory effect of CNP on the ANP secretion in hypertrophied atria may be due to lack of cGMP production. The results showing the relief of CNP-induced negative inhibition of ANP secretion by atrial hypertrophy suggest that CNP may be a contributing factor to delay the development of cardiac hypertrophy.