激动κ阿片受体对大鼠高原性肺水肿的预防效果

Efficacy of acting κ opioid receptor for prevention of high altitude pulmonary edema in rats

目的 评价激动κ阿片受体对大鼠高原性肺水肿的预防效果.方法 雄性SD大鼠40只,8周龄,体重250 ～ 300 g,采用随机数字表法,将其分为5组（n=8）：对照组（C组）、低压低氧组（H组）、生理盐水＋低压低氧组（NH组）、κ阿片受体激动剂U50488H＋低压低氧组（UH组）、选择性κ阿片受体拮抗剂nor-BNI＋U50488H＋低压低氧组（NUH组）.大鼠置于低压低氧舱（大气压355 mmHg,氧分压74 mmHg）2 d以制备高原性肺水肿模型.模型制备前3d,NH组腹腔注射生理盐水0.5 ml,UH组腹腔注射U50488H 1.25 mg/kg,NUH组腹腔注射nor-BNI 2.0 mg/kg,10 min后腹腔注射U50488H 1.25mg/kg,均为每日1次.低压低氧处理2d后,测定平均肺动脉压（mPAP）,取动脉血样,测定血清丙二醛（MDA）和促红细胞生成素（EPO）的水平；随后处死大鼠,取肺组织,计算肺含水量,测定肺组织一氧化氮（NO）、诱导型一氧化氮合酶（iNOS）、MDA、SOD、内皮素-1（ET-1）、血栓素B2 （TXB2）和6-酮-前列腺素F1α（6-keto-PGF1α）的水平,并计算TXB2/6-keto-PGF1α比值.光镜下观察肺组织病理学结果.结果 与C组比较,其余4组大鼠mPAP、肺含水量、肺组织ET-1、MDA、TXB2和6-keto-PGF1α水平、TXB2/6-keto-PGF1α比值和血清MDA和EPO水平升高,肺组织iNOS、NO、SOD水平降低（P＜0.05）；与H组比较,UH组大鼠mPAP、肺含水量、肺组织ET-1、MDA、TXB2和6-keto-PGF1α水平、TXB2/6-keto-PGF1α比值和血清MDA和EPO水平降低,肺组织iNOS、NO、SOD水平升高（P＜0.05）,NH组和NUH组上述指标差异无统计学意义（P＞0.05）.UH组肺组织病理损伤较H组减轻.结论 激动κ阿片受体可对大鼠高原性肺水肿产生预防效果,机制与抑制脂质过氧化反应和纠正缩血管/舒张血管因子失衡有关.

Objective To evaluate the efficacy of acting κ opioid receptor for prevention of high altitude pulmonary edema （HAPE） in rats.Methods Forty male Sprague-Dawley rats,aged 8 weeks,weighing 250-300 g,were randomly divided into 5 groups （n =8 each） using a random number table：control group （group C）,hypobaric hypoxia group （group H）,normal saline ＋ hypobaric hypoxia group （group NH）,U50488H （a selective kappa-opioid receptor agonist） ＋ hypobaric hypoxia group （group UH）,and nor-binaltorphimine （norBNI,a selective kappa-opioid receptor antagonist） ＋ U50488H ＋ hypobaric hypoxia group （group NUH）.The rats were put into the hyperbaric chamber and exposed to hypobaric hypoxia （atmospheric pressure 355 mmHg,partial pressure of oxygen 74 mmHg） for 2 days to induce HAPE.At 3 days before HAPE,normal saline 0.5 ml,U50488H 1.25 mg/kg,and nor-BNI 2.0 mg/kg were injected intraperitoneally once a day in NH,UH,and NUH groups,respectively,and in addition U50488H 1.25 mg/kg was injected intraperitoneally 10 min later in NUH group.After 2 h exposure to hypobaric hypoxia,mean pulmonary artery pressure （mPAP） was detected,and arterial blood samples were collected for determination of serum malondialdehyde （MDA） and erythropoietin （EPO） levels.The rats were then sacrificed and lungs were removed for microscopic examination and for determination of the levels of nitric oxide （NO）,inducible nitric oxide synthase （iNOS）,MDA,superoxide dismutase （SOD）,endothelin-1 （ET-1）,thromboxane B2 （TXB2）,and 6-keto-prostaglandin F1α （6-keto-PGF1α） in lung tissues.Lung water content and TXB2/6-keto-PGF1α ratio was calculated.Results Compared with group C,mPAP,lung water content,ET-1,MDA,TXB2 and 6-keto-PGF1α levels,TXB2/6-ketoPGF1α ratio,and serum MDA and EPO levels were significantly increased,and iNOS,NO and SOD levels were decreased in the other four groups （P 〈 0.05）.Compared with group H,mPAP,lung water content,ET-1,MDA,TXB2 and 6-keto-PGF1α levels,TXB2/6-ketoPGF1α ratio and serum MDA and EPO levels were significantly decreased,and iNOS,NO and SOD levels were increased in UH group （P 〈 0.05）,and no significant changes were found in the indexes mentioned above in NH and NUH groups （P 〉 0.05）.The pathological changes of lung tissues were significantly attenuated in group UH as compared with H group.Conclusion Acting κ opioid receptor can produce prevention for HAPE in rats,and inhibition of lipid peroxidation and correction of the imbalance between vasoconstrictive factors and vasodilative factors may be involved in the mechanism.