Abstract--Carbon monoxide (CO) is produced in the course of heme degradation from biliverdin by heme oxygenase (HO) in various tissues, including the central nervous system. Recent studies suggest the inhibition of HO activity increases arterial pressure mediated by the autonomic nervous system. The present study was designed to investigate the autonomic regulation of cardiovascular responses to inhibition of endogenous CO production by the HO inhibitor Zinc deuteroporphyrin 2, 4-bis glycol (ZnDPBG) by using direct sympathetic nerve recordings in conscious, chronically instrumented rats. ZnDPBG induced increases in mean arterial pressure (MAP) (P<0.05) and renal sympathetic nerve activity (RSNA) (P<0.05) but no significant change in heart rate (P>0.05) in intact rats. In atropine-treated rats, ZnDPBG also induced increases in MAP (P<0.05) and RSNA (P<0.05) but no change in heart rate (P>0.05). In sinoaortic denervated rats, ZnDPBG induced increases in MAP (P<0.05), heart rate (P<0.05), and RSNA (P<0.05). ZnDPBG shifted the baroreflex curve for RSNA upward and to the right, which was characterized by increases in the maximum and minimum response and midpoint pressure without altering the maximum gain. These results indicate that inhibition of HO activity within the central nervous system causes sympathoexcitation, resulting in an increase in arterial pressure. We conclude that the CO/HO system plays an important role in cardiovascular regulation by modulating sympathetic tone.