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.

Natural heme oxygenase-1 inducers in hepatobiliary function

“…The importance of CO as an endogenous modulator of vascular portal perfusion has been confirmed by Pannen et al [31] who demonstrated how NO serves as a potent vasodilator in the hepatic arterial circulation, but exerts only a minor vasodilatory effect in the portal venous vascular bed, while CO does not regulate hepatic artery tone, but is able to maintain portal vascular tone in a relaxed state. Wakabayashi et al [32] have confirmed these results, by showing that the induction of HO-1 with hemin causes a decrease in baseline resistance and in the response to endothelin-1 through an increase in CO production in the extrasinusoidal compartment. We have also shown that overproduction of CO by induction of HO with CoCl 2 , reduces the response to the vasoconstrictor endothelin-1, but not to phenylephrine, in the isolated perfused rat liver [33] .…”

Cystathionine β‐synthase as a carbon monoxide–sensitive regulator of bile excretion†

“…1B). 13 Under these conditions, bile output was modestly but significantly increased at 12 to 18 hours after the treatment (Fig. 1C) in parallel with significant elevation of HCO 3 Ϫ to make bile more alkaline (Fig.…”

“…Their common bile ducts were ligated in proximity to the duodenum, and the gallbladder was nicked and cannulated with a polyethylene P-10 tube to collect bile for 20 minutes after a 10-minute stabilization period. 6,13 Biliary constituents such as total bile salts, bilirubin-IX␣, pH values, and bicarbonate (HCO 3 Ϫ ) were measured according to previous methods described elsewhere. 13 When necessary, biliary samples were collected into tubes containing 10% trichloroacetate to measure glutathione through highperformance liquid chromatography.…”

“…6,13 Biliary constituents such as total bile salts, bilirubin-IX␣, pH values, and bicarbonate (HCO 3 Ϫ ) were measured according to previous methods described elsewhere. 13 When necessary, biliary samples were collected into tubes containing 10% trichloroacetate to measure glutathione through highperformance liquid chromatography. 14 Determination of bilirubin-IX␣ in bile serves as an indicator of HO-mediated heme degradation in the liver that occurs in parallel with endogenous CO generation.…”

Heme Oxygenase–1: A Cellular Hercules

“…9,10 Physiologically, HO-1 is involved in modulation of hepatic sinusoidal tone and portal venous regulation. 11,12 These effects are thought to be secondary to the generation of CO, activation of guanylyl cyclase, and subsequent production of cyclic guanosine monophosphate, similar to that of NO. The importance of HO-1 in hepatobiliary vascular regulation is emphasized under pathologic conditions of portal hypertension, in which expression of HO-1 is increased significantly.…”