Carbon monoxide (CO) generated by heme oxygenase has recently been considered a neural messenger in brain. This observation prompted us to investigate whether CO participates in vascular regulation in the liver, another organ with high levels of heme oxygenase activity. In isolated perfused rat liver, submicromolar levels of CO were detectable in the effluent and were able to be suppressed by the administration of Zn protoporphyrin IX (1 microM), a potent inhibitor of heme oxygenase. Furthermore, zinc protoporphyrin IX (1 microM) promoted an increase in the perfusion pressure under the constant flow conditions. These changes were reversed by adding CO (2 microM) or a cGMP analogue 8-bromo-cGMP (1 microM) in the perfusate. The present findings indicate that CO can function as an endogenous modulator of vascular perfusion in the liver.