洛沙坦对高肺血流量大鼠肺血管平滑肌增殖及肺小动脉重构的抑制作用

Effects of Losartan on proliferation of the pulmonary vascular smooth muscle cells and pulmonary vascular remodeling induced by high pulmonary blood flow in rats

目的观察血管紧张素受体拮抗剂对高肺血流量导致肺动脉高压肺血管重构的影响。方法采用腹主动脉-下腔静脉瘘制造大鼠容量负荷性肺动脉高压模型，并应用洛沙坦（10sartan）进行干预，6周后观察肺动脉收缩压（PASP）、舒张压（PADP）、右室收缩压（PVSP）变化，心室重量变化，肺血管平滑肌细胞（VSMC）α-平滑肌肌动蛋白（α-actin）及增殖细胞核抗原（PCNA）免疫组化染色；比较各组α-actin积分光密度值（IOD）及肺血管VSMC的PCNA阳性率，比较无肌性动脉肌性化程度及肺小动脉血管厚度百分比（％WT）。结果手术组动物RVSP、PASP、PADP较对照组明显升高（P〈0．05），手术＋洛沙坦组RVSP、PASP、PADP明显低于手术组（P〈0．05）；手术组右心室（RV）／左心室加室间隔（LV＋S）、RV／体重（BW）、（LV＋S）／BW较对照组显著增加（P〈0．001），而手术＋洛沙坦组则较手术组显著降低（P〈0．01）。与对照组比较，手术组α-actin染色IOD值显著降低（P〈0．01），而手术＋洛沙坦组IOD值则高于手术组（P〈0．05），手术组细胞PCNA阳性率显著升高（P〈0．01），而手术＋洛沙坦组低于手术组（P〈0．05）；手术组与其他两组比较，管经50～100μm、101～150μm％WT及15～50μm血管肌性化百分比显著增加（P〈0．01）。结论腹主动脉一腔静脉分流导致了肺血管重构和肺动脉高压的发生，洛沙坦能有效地抑制高肺血流量大鼠肺动脉VSMC增殖，减缓肺动脉高压肺血管重构进程。

Objective To investigate the effect of angiotensin Ⅱ receptor antagonist on the pulmonary arteries hypertension and pulmonary vascular remodeling induced by high pulmonary blood flow. Methods Thirty-six male SD rats were randomly divided into shunt plus Losartan group（hereafter named Losartan group）,shunt group and control group. An arterial-venous shunt was surgically created between the abdominal aorta and inferior vena cava in rats of Losartan group and shunt group. The models of capacity load pulmonary arteries hypertension were made. Losartan was given to the models. Six weeks after the operation, pulmonary artery systolic pressure（PASP）, pulmonary artery diastolic pressure （PADP） and right ventricular systolic pressure（RVSP） of all rats were measured with cardiac catheterization. The animals＇ hearts were measured to calculate the ratio of right ventricle mass to left ventricle plus septum mass（RV/ LV ＋ S） body weight normalized mass to right ventricle mass（RVBW） and left ventricle plus septum mass （LV ＋ S/BW） . Immunohistochemical stains were used to show α-actim, pulmonary vascular smooth muscle cells, proliferation cells nuclear antibody（PCNA）, and elastin distribution in pulmonary arteries. The comparisons of the IOD, the positive ratio of PCNA in VSMC in pulmonary vessels,and morphometric parameters （percent vascular wall thickness in small arteries of the lungs, muscularization） among three groups were made to assess the remodeling of small pulmonary arteries. Results In comparison with the control group, PASP, PADP, RVSP were obviously elevated（P〈 0.05） and RV/（LV ＋ S）, PV/BW, （LV ＋ S）/BW were also significantly elevated in shunt group （P 〈 0.001）. In the Losartan group, PASP, PADP, RVSP and RV/（LV ＋ S）, RV/BW, （LV ＋ S）/BW were the lowest（ P 〈 0.05, P 〈 0.01, respectively ）. While α-actin IOD was lower （ P〈0.01） and the positive ratio of PCNA was significantly higher in shunt group （P〈0.01）. However, α-actin IOD was higher and the positive ratio of PCNA was lower in Losartan group. Muscularization of small pulmonary arteries and pulmonary artery medial hypertrophy（wall thickness） was obviously increased in shunt group（P〈0.01） than other two groups. Conclusions Abdominal aorta and inferior vena fistula results in pulmonary hypertension and pulmonary vascular remodeling. Losartan could slow down pulmonary hypertention and remodeling development in rats by inhibiting the proliferation of pulmonary VSMC induced by high pulmonary blood flow.