摘要
目的观察磷酸二酯酶V抑制剂西地那非对肺动脉高压大鼠肺血管重塑的影响及其机制。方法40只SD大鼠,体重220～230 g,随机分为4组(n=10)：对照组(C组)、肺动脉高压组(P组)、盐酸西地那非25 mg·kg^(-1)(S1组)、盐酸西地那非50 mg·kg^(-1)组(S2组)。P组、S1组、S2组腹腔注射野百合碱60 mg·kg^(-1)(用生理盐水稀释至1ml),C组给予等量生理盐水。S1组、S2组注射野百合碱后2周腹腔注射相应剂量的盐酸西地那非,每天1次,给药时间持续6周。测定平均动脉压(MAP)及平均肺动脉压(MPAP)后处死大鼠,计算右心室壁重量与左心室+室间隔之和的比值(右心室肥厚指数),光镜下观察肺组织的形态学,计算肺小动脉管壁与管腔厚度的比值(管壁/管腔比),用RT-PCR方法测定肺组织血管内皮生长因子(VEGF)mRNA表达,用Western blot方法测定肺组织总ERK_1/ERK_2、磷酸化ERK_1/ERK_2及MKPl水平。结果野百合碱可导致MPAP、右心室肥厚指数及肺小动脉管壁/管腔比增加,并可增加肺组织VEGF mRNA、磷酸化ERK_1/ERK_2、MKP1水平,但是对MAP无影响,西地那非除增加肺组织MKP1水平外,可减弱野百合碱诱发的上述改变。结论西地那非可减轻肺动脉高压大鼠的肺血管重塑,其机制与下调肺组织VEGF、ERK_1/ERK_2磷酸化水平有关。
Objective To investigate the effects of sildenafil on pulmonary vascular remodeling in a rat model of pulmonary hypertension and the possible mechanism. Methods Forty SD rats weighing 220-230 g were randomly divided into 4 groups （ n = 10 each） ; group Ⅰ control （C） ; group Ⅱ pulmonary hypertension （PH） ; group Ⅲ sildenafil 25 mg·kg^-1·d^-1 ＋ PH （S1） and group Ⅳ sildenafil 50 mg·kg^-1·d^-1＋ PH （S2）. Pulmonary hypertension was induced by intraperitoneal injection of monocrotaline 60 mg· kg^- 1 （ in normal saline 1 ml） in group PH, S1 and S2 （ group Ⅱ , Ⅲ and Ⅳ ）. In control group normal saline 1 ml was given IP instead of monocrotaline. Fourteen days after IP monocrotaline sildenafil was given IP every day for 6 weeks. The animals were then tracheostomized, intubated and mechanically ventilated under pentobarbital anesthesia. Left common carotid artery and pulmonary artery （through right ventricle） were cannulated for MAP and MPAP monitoring. The animals were then killed and the hearts and lungs were removed. Right ventricular hypertrophy index （ the ratio between the weight of right ventricle and the total weight of left ventricle and septum RV/LV ＋ S） and the ratio between the thickness of the wall and the diameter of the lumen of pulmonary arterioles were calculated. The lung tissues were examined with light microscope. The expression of vascular endothelial growth factor （VEGF） mRNA （by RT-PCR）, ERK1/ERK2 and MKP1 （by western blot） in the lung were determined. Results Monocrotaline could induce pulmonary hypertension, pulmonary vascular remodeling and upregulate expression of VEGF mRNA, phosphorylated ERK1/ERK2 and MKP1. Sildenafil could attenuate the changes induced by monocrotaline as mentioned above except up-regulation of MKP1 expression in the lung. Conclusion Sidenafil, a phosphodiesterase type 5 inhibitor, can attenuate pulmonary vascular remodeling induced by pulmonary hypertension. The down- regulation of expression of VEGF mRNA and phosphorylated ERK1/ERK2 is involved in the mechanism.
出处
《中华麻醉学杂志》
CAS
CSCD
北大核心
2006年第8期725-729,共5页
Chinese Journal of Anesthesiology
基金
上海市科委重大项目(024119001)
关键词
磷酸二酯酶抑制剂
高血压
肺性
肺动脉
Phosphodiesterase inhibitors
Hypertension, pulmonary
Pulmonary artery.
