Roles of low molecular ononoxides in regulation of hepatobiliary function

血红素加氧酶是一种血红素氧化酶，产生胆绿素和一氧化碳。本研究旨在阐明由该酶内源性产生的CO是否在肝脏微循环中起到活性血管松弛剂的作用。采用双色数字显微荧光技术交替监测离体灌注大鼠肝脏的微血管结构，以监测窦状动脉内膜和脂肪储存的Ito细胞。在对照肝脏中，静脉流出物的CO通量为0.7 nmol/min /g肝脏。给药血红素加氧酶抑制剂原卟啉锌IX （1mum）消除了基线CO生成，血管阻力显示出30%的升高，同时鼻窦收缩和鼻窦灌注速度降低。收缩的主要部位对应于与Ito细胞共定位的局部正弦段，通过成像其维生素A自身荧光来识别。在灌注液中加入CO （1 muM）或cGMP类似物8-溴-cGMP （1 muM）可明显减弱血管阻力和血管收缩的增加。根据这些发现，我们提出CO可以通过涉及Ito细胞的放松机制作为肝窦灌注的内源性调节剂。

Heme oxygenase is a heme-oxidizing enzyme which generates biliverdin and carbon monoxide (CO). The present study was designed to elucidate whether CO endogenously produced by this enzyme serves as an active vasorelaxant in the hepatic microcirculation. Microvasculature of the isolated perfused rat liver was visualized by dual-color digital microfluorography to monitor sinusoidal lining and fat-storing Ito cells, alternately. In the control liver, the CO flux in the venous effluent ranged at 0.7 nmol/min /g liver. Administration of a heme oxygenase inhibitor zinc protoporphyrin IX (1 muM) eliminated the baseline CO generation, and the vascular resistance exhibited a 30% elevation concurrent with discrete patterns of constriction in sinusoids and reduction of the sinusoidal perfusion velocity. The major sites of the constriction corresponded to local sinusoidal segments colocalized with Ito cells which were identified by imaging their vitamin A autofluorescence. The increase in the vascular resistance and sinusoidal constriction were attenuated significantly by adding CO (1 muM) or a cGMP analogue 8-bromo-cGMP (1 muM) in the perfusate. From these findings, we propose that CO can function as an endogenous modulator of hepatic sinusoidal perfusion through a relaxing mechanism involving Ito cells.