Heme oxygenase and hepatic microcirculation: more than just carbon monoxide?

(cGMP). Like NO , CO can also activate guanylate cyclase to cause vasodilation [5] ; however, previous studies have indicated that other mechanisms may contribute to the effects of CO on hepatic tone [6] . In their study [4] , the authors found some potentially novel mechanisms by which HO-1 mediates hepatic tone that appear independent of cGMP and, at least in part, independent of CO . The authors employed the isolated perfused rat liver. Although this model does not recapitulate all aspects that regulate hepatic tone (e.g. the liver is not innervated), the advantages of this perfusion model outweigh the limitations. Specifically, all normal intrahepatic communications are assumedly intact in an organ in which the perfusion flow is mimicking the in vivo situation [7] . The authors showed that the TLR agonist zymosan A caused a robust increase in portal pressure [see fig. 1a, 4 ] that is rapidly, albeit incompletely, compensated by the liver. Under these conditions, NO did not appear to play a primary role in the portal pressure changes; although inhibiting NOS with L -NAME increased the pressure response caused by zymosan A, the shape of the curve was not altered and the pressure returned to almost basal within a similar timeframe. Likewise, adding exogenous cGMP (8-Br-cGMP) did not alter the increase in portal pressure caused by zymosan A, although it blunted the L -NAME effect. Hepatic microcirculatory tone is a complex and dynamic process that is mediated by the balance of local and systemic vasoconstrictor and vasodilators. Dysregulation of hepatic microcirculatory tone is not only involved in acute liver injury (e.g. hemorrhagic shock, ischemia/ reperfusion injury, organ transplantation, etc.) [1] , but is also responsible for many of the sequelae associated with chronic liver diseases (e.g. ascites, esophageal varices, etc.) [2] . Therefore, understanding of the mechanisms behind the maintenance of this tone has direct implications to several clinical situations. Activated Kupffer cells release several vasoactive compounds that can directly or indirectly alter hepatic vascular tone. Indeed, in previous work, Steib et al. [3] demonstrated that activation of Kupffer cells (the resident hepatic macrophages) with zymosan A, causes hepatic vasoconstriction mediated, at least in part, by thromboxane A 2 (TxA 2 ). Here [4] , the authors build on this model and investigate the role of nitric oxide (NO ) from nitric oxide synthases (NOS) and carbon monoxide (CO ) from heme oxygenase-1 (HO-1) in mediating hepatic microcirculatory changes under these conditions. Both gases are vasodilators that have been shown to rescue livers from vasoactive stimuli in several models. NO is assumed to mediate its effects predominantly via activating guanylate cyclase to produce cyclic guanosine monophosphate Published online: January 16, 2013