Heller J, Sogni P, Tazi K A, Chagneau C, Poirel O, Moreau R, Lebrec D
Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, Hôpital Beaujon, Clichy, France.
Hepatology. 1999 Sep;30(3):698-704. doi: 10.1002/hep.510300301.
Hyporeactivity to vasoconstrictors in aortae from portal vein-stenosed rats is associated with an increased activity of endothelial NO synthase (NOS3). In contrast, during sepsis, which is common in cirrhosis, vascular hyporeactivity is associated with an induction of inducible NOS2. The aim of this study was to investigate the in vitro reactivity to phenylephrine and the regulation of NOS2 and NOS3 in aortae from portal vein-stenosed rats after lipopolysaccharide (LPS) administration. Aortic vascular reactivity for phenylephrine, aortic NOS activity, and NOS2 and NOS3 protein expression were determined 5 hours after intravenous LPS or saline administration. Moreover, aortic NOS activity was measured after 5-hour in vitro incubation in LPS. LPS induced a significantly smaller decrease in aortic tension in portal vein-stenosed than in sham-operated rats. Under baseline conditions, aortic NOS activity and NOS3 protein expression were higher in portal vein-stenosed than in sham-operated rats, and NOS2 protein expression was not detected in aortae from either group. After LPS administration, NOS activity and NOS2 protein expression increased significantly less in portal vein-stenosed than in sham-operated rat aortae. Similar results were obtained after in vitro incubation with LPS. Endothelium removal or NOS3 inhibition with the calmodulin inhibitor, W7, increased NOS activity in the aortae of portal vein-stenosed rats after LPS incubation. In conclusion, in aortae of portal vein-stenosed rats exposed to LPS, no further decrease in aortic reactivity to phenylephrine was observed, and the induction of NOS2 was down-regulated. Endothelium removal or calmodulin inhibition inhibits NOS3 overactivity and leads to normalized NOS2 activation after LPS in aortae from portal vein-stenosed rats.
门静脉狭窄大鼠主动脉对血管收缩剂反应性降低与内皮型一氧化氮合酶（NOS3）活性增加有关。相反，在肝硬化常见的脓毒症期间，血管反应性降低与诱导型一氧化氮合酶（NOS2）的诱导有关。本研究的目的是调查脂多糖（LPS）给药后门静脉狭窄大鼠主动脉对去氧肾上腺素的体外反应性以及NOS2和NOS3的调节情况。静脉注射LPS或生理盐水5小时后，测定主动脉对去氧肾上腺素的血管反应性、主动脉NOS活性以及NOS2和NOS3蛋白表达。此外，在LPS中体外孵育5小时后测量主动脉NOS活性。与假手术大鼠相比，LPS诱导门静脉狭窄大鼠主动脉张力的降低明显更小。在基线条件下，门静脉狭窄大鼠主动脉的NOS活性和NOS3蛋白表达高于假手术大鼠，两组大鼠的主动脉均未检测到NOS2蛋白表达。给予LPS后，门静脉狭窄大鼠主动脉的NOS活性和NOS2蛋白表达的增加明显少于假手术大鼠。LPS体外孵育后也获得了类似结果。去除内皮或用钙调蛋白抑制剂W7抑制NOS3可增加LPS孵育后门静脉狭窄大鼠主动脉的NOS活性。总之，在暴露于LPS的门静脉狭窄大鼠主动脉中，未观察到主动脉对去氧肾上腺素反应性的进一步降低，且NOS2的诱导被下调。去除内皮或抑制钙调蛋白可抑制NOS3的过度活性，并导致LPS作用后门静脉狭窄大鼠主动脉中NOS2的激活恢复正常。
