NOS和COX抑制剂对PHT鼠COX表达和血流动力学的影响

Influence of NOS and COX Blocker on the Expression of COX and Hemodynamics in PHT Rats

目的探讨在门静脉高压症高动力循环发生发展中前列环素(PGI2)的作用以及一氧化氮(NO)和PGI2之间的关系。方法将肝内型门脉高压(IHPH)、肝前型门脉高压(PHPH)和手术对照(SO)三组大鼠模型,分别使用生理盐水、长短期N-硝基-L-精氨酸(L-NNA)和长短期吲哚美辛(INDO)治疗后,行血流动力学研究,采取股动脉血行血浆6-keto-PGF1α和NO2-/NO3-浓度检测,并测定内脏和血管组织中COXmRNA的表达。结果与生理盐水对照组比较,长短期应用L-NNA和INDO均能显著改善门脉高压鼠的高动力循环状态(P<0.05),并显著降低血浆6-keto-PGF1α和NO2-/NO3-浓度(P<0.05);应用L-NNA长期较短期的内脏血流动力学明显改善(P<0.05),但内脏和血管组织COX-1mRNA表达增加和血浆6-keto-PGF1α浓度明显升高(P<0.05);应用INDO长期与短期比较,内脏血流动力学仍呈现高血流动力学状态(P<0.05),血浆NO2-/NO3-浓度显著性升高(P<0.05)。结论在门静脉高压症高动力循环中PGI2和NO之间存在相互作用,其高血流动力学状态主要与NO有关。

Objective To investigate the possible interaction between prostacyclin （PGI2） and nitric oxide （NO） in the hyperdynamic circulatory state of chronic portal hypertensive rats. Methods Ninety-seven male SpragueDawley rats were divided into three groups, namely, intrahepatic portal hypertension （IHPH） , prehepatic portal hypertension （PHPH） and sham-operated controls （SO）. Animals of each group received N^ω-nitro-L-arginine （LNNA） or indomethacin （INDO） either on a short term （7 d） or long term （15 d） with saline as control. Splanchnic hemodynamics was measured by radioactive microsphere techniques. The concentration of NO in serum was determined by nitrates ＋ intrites which were measured by the colorimetric method and that of PGI2 was done by using specific radioimmunoassay for its stable hydrolysis product 6-keto-PGF1α. RT-PCR was performed to measure the levels of COX-lmRNA in the superior mesenteric artery and thoracic aorta. Results Compared with saline treated rats, short-term or long-term L-NNA treatment could decrease COX-1 mRNA expression in splanchnic vessels and intestine. Concomitantly, there was a significant decrease in the concentration of plasma 6-keto-PGF1α and serum nitrates ＋ nitrites in IHPH and PHPH rats （P 〈0.05）. At the same time, portal venous inflow （PVI） was lowered down but splanchnic vascular resistance （SVR） increased （P 〈 0.05）. In both IHPH and PHPH rats, the COX-1 mRNA expression and the concentration of plasma 6-keto-PGF1α after nitric oxide synthase （NOS） blockade for the long term were higher than the levels of continuous blockade NOS for the short term, whereas there was significant difference in hemodynamic parameters such as PVI and SVR. Concentrations of plasma 6-keto-PGF1α long term were no more than the levels of continuous blockade COX for the short term, after INDO blockade for the whereas hemodynamics restored the splanchnic hyperdynamic circulatory state. Conclusion There is a possible interaction between PGI2 and NO in the hyperhemodynamics of portal hypertension. NO is the mediator in the formation and development of hyperdynamic circulatory state in chronic portal hypertensive rats.