To define the long-term effects of pentobarbital sodium on the plasma and atrial atrial natriuretic peptide (ANP) system, experiments were performed in female Sprague-Dawley rats. The plasma levels of immunoreactive (ir) ANP showed chronic as well as acute response to pentobarbital sodium administration. A single dose (30 mg/kg, i.p.) of pentobarbital sodium resulted in a suppression in the plasma levels of irANP up to 1 week of administration. The suppressive effect on plasma irANP concentrations was dose-dependent. Right but not left atrial contents of irANP increased by an administration of pentobarbital sodium up to 4 weeks. ANP mRNA contents of the atrial exposed to pentobarbital sodium began to increase after 2 days, reached to the peak after 2 weeks, and began to return to control values after 6 weeks. Surgical stress accentuated these patterns of plasma and atrial ANP responses to pentobarbital sodium treatment. The present data, therefore, suggest that even a single anesthetic dose of pentobarbital could elicit long-lasting profound changes in ANP system, i.e., changes in gene expression, synthesis and the secretion of ANP.