Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats.

Abstract

Maintenance of hepatic microcirculatory flow after ischemia of the liver is essential to prevent hepatic dysfunction. Thus, we determined the differential role of carbon monoxide (CO) and nitric oxide (NO) in the intrinsic control of sinusoidal perfusion, mitochondrial redox state, and bile production in the isolated perfused rat liver after hemorrhagic shock. Administration of tin protoporphyrin-IX (50 M), a specific inhibitor of the CO generating enzyme heme oxygenase, caused a decrease in sinusoidal flow that was more pronounced after shock compared with sham shock, as determined by in situ epifluorescence microscopy. This was associated with a shift in hepatocellular redox potential to a more reduced state (increased fluorescence intensity of reduced pyridine nucleotides in hepatocytes, decreased acetoacetate/ ␤ -hydroxybutyrate ratio in the perfusate) and a profound reduction in bile flow. In sharp contrast, the preferential inhibitor of the inducible isoform of NO synthase S-methylisothiourea sulfate (100 M) did not affect sinusoidal flow, hepatic redox state, or function. This indicates that 1.) endogenously generated CO preserves sinusoidal perfusion after hemorrhagic shock, 2.) protection of the hepatic microcirculation by CO may serve to limit shock-induced liver dysfunction, and 3.) in contrast to CO, inducible NO synthase-derived NO is of only minor importance for the intrinsic control of hepatic perfusion and function under these conditions. ( J. Clin Invest. 1998. 102:1220-1228.)

Initiation of remote hepatic injury in the rat: Interactions between Kupffer cells, tumor necrosis factor-α, and microvascular perfusion

“…Increases in heterogeneity may result from sinusoidal narrowing caused by edema or vascular responses mediated by liver-specific pericytes (Ito cells). 32,33 Additionally, leukocytes have often been implicated in the microvascular perfusion deficits observed during various inflammatory states. 34 Although such mechanisms were not directly tested, the results from the present study support the hypothesis that Kupffer cell activation along hepatic sinusoids may contribute to the development of hepatic microvascular perfusion heterogeneity.…”

Nitric oxide in liver injury

“…In certain injuries, such as that accompanying hemorrhagic shock and resuscitation, inhibition of HO-1, but not NOS, impairs sinusoidal perfusion and exacerbates injury. 37 HO-1 induction is reportedly protective also in sepsis. 38 Thus, NO and carbon monoxide both may help protect sinusoidal perfusion after injury, although their respective roles may vary with the type of injury.…”

Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury

“…Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an internal control, was obtained from MPCR Kit for rat apoptosis genes set-2 (Maxim Biotech, San Francisco, Calif., USA). They were amplified in 25 pl of PCR reaction volume containing 1.8 pmol of MgC12, 25 mmol of KCI, and 10 mmol of Tris buffer using 1 mg of cDNA templates. PCR products of HO-1 were 451 base pairs.…”