Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy.
J Hepatol. 2011 Feb;54(2):258-64. doi: 10.1016/j.jhep.2010.08.013. Epub 2010 Sep 18.
BACKGROUND & AIMS: Heme oxygenase (HO) catabolizes heme into biliverdin, carbon monoxide (CO), and free iron. CO generated in endothelial and smooth muscle layers of blood vessels modulates vascular tone by inducing relaxation of vascular smooth muscle cells. The aim of this study was to verify the role played by HO in regulating renal arterial resistance and Na(+) excretion in cirrhosis.
Twenty control rats and 20 rats with CCl(4)(-) induced cirrhosis, 10 of which were chronically treated with the HO inducer cobalt-protoporphyrin (CoPP), were studied. Pressurized renal interlobar arteries were challenged with increasing doses of phenylephrine (PE) and acetylcholine (ACh). Dose-response curves were evaluated under basal conditions and after inhibition of HO with chromium-mesoporphyrin (CrMP). HO-1 (inducible form) and HO-2 (constitutive form) expression was measured in the main and interlobar renal arteries. Serum and urinary levels of Na(+) and creatinine were also evaluated.
In renal interlobar arteries from cirrhotic rats, the response to PE was increased, while that to ACh was blunted. After HO inhibition, the responsiveness to these vasoactive substances was comparable in the two groups. In cirrhotic rats, HO-1 expression was impaired in the main and the interlobar renal arteries. Chronic HO induction normalized the response to the vasoconstrictor, but not to the vasodilator. Cirrhotic rats treated with CoPP showed higher urinary Na(+) concentration and fractional Na(+) excretion, compared to both untreated cirrhotic and control rats.
In cirrhotic rats, an impaired HO-1 expression promotes vasoconstriction of renal interlobar arteries. Chronic HO induction normalizes the sensitivity to PE and promotes Na(+) excretion.
血红素加氧酶（HO）可将血红素分解为胆红素、一氧化碳（CO）和游离铁。血管内皮和平滑肌层产生的 CO 通过诱导血管平滑肌松弛来调节血管张力。本研究旨在验证 HO 在调节肝硬化时肾动脉阻力和 Na(+)排泄中的作用。
本研究共纳入 20 只正常大鼠和 20 只 CCl(4)(-)诱导的肝硬化大鼠，其中 10 只肝硬化大鼠接受慢性 HO 诱导剂钴原卟啉（CoPP）治疗。用苯肾上腺素（PE）和乙酰胆碱（ACh）递增剂量刺激加压肾叶间动脉，在基础状态下以及用 HO 抑制剂铬mesoporphyrin（CrMP）处理后评价剂量-反应曲线。在主肾动脉和叶间肾动脉中测量 HO-1（诱导型）和 HO-2（组成型）的表达。还评估血清和尿中 Na(+)和肌酐的水平。
在肝硬化大鼠的叶间肾动脉中，PE 的反应增强，而 ACh 的反应减弱。HO 抑制后，两组对这些血管活性物质的反应性相当。在肝硬化大鼠中，主肾动脉和叶间肾动脉的 HO-1 表达受损。慢性 HO 诱导使对血管收缩剂的反应正常化，但对血管扩张剂的反应无影响。与未治疗的肝硬化大鼠和正常大鼠相比，接受 CoPP 治疗的肝硬化大鼠的尿 Na(+)浓度和 Na(+)排泄分数更高。
在肝硬化大鼠中，HO-1 表达受损促进肾叶间动脉收缩。慢性 HO 诱导使对 PE 的敏感性正常化，并促进 Na(+)排泄。
