Carbon monoxide overproduced by heme oxygenase-1 causes a reduction of vascular resistance in perfused rat liver.

Abstract

This study aimed to examine whether livers overexpressing heme oxygenase (HO)-1 could alter the vascular resistance through the vasorelaxing action of carbon monoxide (CO). The relationship among HO-1 expression, CO generation, and the vascular resistance was assessed in perfused rat livers pretreated with hemin, an inducer of HO-1. At 18 h after the hemin treatment, livers displayed marked increases in HO-1 expression in hepatocytes and venous CO flux and a reduction of the basal resistance. The reduction of the resistance in hemin-treated livers was canceled by administration of oxyhemoglobin, a reagent trapping both CO and nitric oxide (NO), but not by methemoglobin, which captures NO but not CO. Liposome-encapsulated oxyhemoglobin, which cannot access the space of Disse, did not cause vasoconstriction. Furthermore, these livers became less sensitive to endothelin-1, a vasoconstrictive peptide, than the untreated controls through mechanisms involving CO. On the other hand, at 12 or 24 h after the treatment when the HO-1 induction was not accompanied by CO overproduction, neither a decrease in the basal resistance nor vascular hyporeactivity to endothelin-1 was observed. These results suggest that CO overproduced in the extrasinusoidal compartment is a determinant of the HO-1-mediated vasorelaxation in the liver.