For a long time carbon monoxide (CO) has been considered as a deadly toxic gas. However, during the last two decades CO has become recognized as an important endogenous signaling compound regulating a number of physiological functions. It is produced in the organism as a by-product of heme degradation catalyzed by heme oxygenases (HOs). Although CO is a potent vasodilator and can also modulate cardiac inotropy, little is known about its effects on cardiac electrical activity. In the present study electrophysiological effects of CO and one of their possible mechanisms were examined in murine working myocardium and sinoatrial node.Standard microelectrode technique was used for registration of myocardial action potentials (APs). RT-PCR assays were performed to estimate expression levels of phosphodiesterases (PDEs) in murine myocardium.Exogenous CO (10-4-10-3M) decreased AP duration in atrial and ventricular tissue and accelerated pacemaking activity in the sinoatrial node by facilitating diastolic depolarization. Inhibitors of heme oxygenases (zinc and tin protoporphyrin IX, 10-5M), which are responsible for endogenous CO production, induced the opposite effects. Therefore, endogenous CO probably acts in the same way as exogenous.Inhibitor of soluble guanylate cyclase (sGC) ODQ (10-5M) suppressed CO effects more than twice, while sGC activator azosidnone (10-5M-3×10-4M) and membrane-permeable cGMP analog BrcGMP (3×10-4M) induced the same effects as CO. Thus, cGMP-dependent signaling mechanism participates in the mediation of cardiotropic CO effects. But why effects of CO are positive in pacemaker and negative in the working myocardium. The answer is probably in the different activity of phosphodiesterase subtypes in these types of cardiac tissue. Milrinone (2×10-6M), selective inhibitor of phosphodiesterase3 (PDE3), which is negatively regulated by cGMP, blocked CO-induced rhythm acceleration. In contrast to PDE3, PDE 2 is positively regulated by cGMP. Selective inhibitor of PDE2 EHNA (2×10-6M) attenuated CO-induced AP shortening, but not the positive chronotropic effect. Therefore, PDE2 activity prevails in working myocardium, while PDE3 is more active in pacemaker. However, this fact cannot be explained by difference in expression of PDE isoforms. We have found that PDE3 mRNA is more abundant than PDE2 mRNA in all studied regions of the heart (sinoatrial node, right auricle and right ventricular wall).The results suggest that cardiac effects of CO are at least partly attributed to activation of sGC and subsequent elevation of cGMP intracellular content. This leads to inhibition of PDE3, increased cAMP content and positive effects in the sinoatrial node, while PDE2 stimulation in working myocardium enhances cAMP degradation and produces negative effects.