内皮素双受体拮抗剂在实验性急性肺栓塞中的应用研究

The application of a dual receptor antagonist of endothelin in experimental acute pulmonary embolism

目的观察静脉内皮素双受体拮抗剂RO2610612在急性肺栓塞中的应用效果,研究内皮素与急性肺栓塞的关系。方法12只健康杂种犬随机分为对照组和实验组,每组6只。两组所有动物给予戊巴比妥静脉麻醉后分别于颈静脉插入热稀释漂浮导管连接生理监护仪;气管内插入气管插管连接呼吸描记器。采集栓塞前数据后于颈静脉注射自体血栓建立急性肺栓塞动物模型。实验组建立模型后1h开始持续静滴RO26106120.2mg/(kg.h),对照组同时输入等量生理盐水。对照组及实验组所有动物于栓塞前、栓塞后1,2,4,6h记录体、肺循环血流动力学指标、呼吸生理指标;取股动脉血3ml,采用放射免疫法测定动脉血内皮素-1水平,并测动脉血气。结果两组动物栓塞后较栓塞前血浆内皮素-1水平、肺动脉平均压、肺血管阻力、呼吸频率、动脉血二氧化碳分压和肺气道阻力显著性升高(P<0.05),心输出量、动脉血氧分压和肺动态顺应性显著性下降(P<0.05)。实验组于栓塞2h后肺动脉平均压、肺血管阻力、呼吸频率、肺气道阻力升高水平显著性低于同时期对照组(P<0.05),血浆内皮素-1水平、心输出量、和肺顺应性显著性高于对照组(P<0.05)。结论在急性肺栓塞病理过程中,内皮素参与了肺循环阻力升高与肺气道阻力升高和肺顺应性下降的形成。内皮素受体拮抗剂拮抗内皮素与其受体的结合,在急性肺栓塞中,可以减缓肺循环阻力、肺气道阻力的上升,因而可能成为急性肺栓塞临床治疗的新手段。

Objective To investigate the effect of application of RO2610612,a dual receptor antagonist of endothelin （ET）, on experimental acute pulmonary embolism （APE） ,and to study the relation between endothelin and APE. Methods Twelve dogs were randomly assigned to a control group（n=6）and a RO2610612 group（n=6）and anesthetized with pentobarbital sodium. For each animal, a thermodilution balloon-tipped pulmonary artery catheter was inserted into the left external jugular vein and connected to a physiological monitor. A polyethylene cannula was intubated into the trachea and connected to a pneumotachograph. After measuring the parameters before emolization, the autologous blood clot was injected to the right jugular vein of each dog to establish the aminal model. For experimental group, RO2610612 was injected ivgtt with the dose of 0.2mg/（kg · h） 1 h after APE, while for control group the same amount of saline was given. Pulmonary and systemic hemodynamic parameters, respiratory physiological parameters, arterial blood, ET-1 concentration and arterial blood gas analysis were determined before embolization and 1,2,4,6 h after embolization. Results Plasma ET-1 levels , mean pulmonary arterial pressure（MPAP）, pulmonary vascular resistance （PVR）, respiratory rate（RR）, pulmonary airway resistance（RL ） and arterial carbon dioxide pressure（PaCO2 ） increased（P〈0.05） , while the cardiac output（CO）, the arterial blood oxygen pressure（PaO2 ） and the dynamic compliance of the respiratory system（Cdyn） decreased significantly after embolization in both groups compared with the data before embolization（P〈0. 05）. In RO2610612 group, MPAP, PVR, RR, RE were significantly lower compared with the control group （P〈0.05） ,ET-1 levels ,CO and Cay, were significantly higher compared with the control group（P〈0.05） 2 h afer embolization. Conclusion Endothelin partially contributes to the hemodynamic derangement and the bronchoconstriction of APE. A dual receptor antagonist of endothelin can attenuate the increase in the pulmonary vascular resistance and pulmonary airway resistance and might serve as a useful therapeutic drug for APE.