一氧化氮和内皮素-1在大鼠野百合碱诱导的肺动脉高压中的作用

Role of nitric oxide and endothelin-1 in monocrotaline-induced pulmonary hypertension in rats.

作者信息

Mathew R, Zeballos G A, Tun H, Gewitz M H

机构信息

Section of Pediatric Cardiology, New York Medical College, Valhalla 10595, USA.

出版信息

Cardiovasc Res. 1995 Nov;30(5):739-46.

DOI:

PMID:8595621

Abstract

OBJECTIVE

Nitric oxide (NO) and endothelin-1 (ET-1) have both been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, we examined NO-related relaxation and ET-1 levels in rat hilar pulmonary arteries (PA) during the progression of monocrotaline (MCT)-induced PH.

METHODS

Rats were studied 1 and 2 weeks after a single subcutaneous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), NO-related relaxation and tissue ET-1 levels in PA were evaluated and compared with control (C).

RESULTS

One week post-MCT, endothelium (E)-dependent relaxation to 10(-5) M adenosine diphosphate (ADP), 10(-5) M A23187 and 10(-5) M acetylcholine (ACh) and tissue ET-1 levels in PA were normal. Rats in this group did not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation was impaired (ADP, 7 +/- 3% VS. c, 62 +/- 5%; A23187, 2 +/- 7% vs. C, 58 +/- 2%; ACh, 33 +/- 7% vs. C, 86 +/- 2%; P < 0.05) and ET-1 levels were elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.05), In addition, significant PH and RVH were present (PAP 33 +/- 4 mmHg vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.25 +/- 0.01, P < 0.05). Incubation with 10 microM indomethacin, 150 U/ml superoxide dismutase or 300 microM L-arginine failed to restore impaired relaxation to ACh. In E-intact rings, relaxation to 10(-6) M glyceryl trinitrate (GTN) was inhibited at 1 week post-MCT (72 +/- 2% vs. C, 87 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Response to GTN in E-denuded rings was normal in MCT groups.

CONCLUSIONS

These results indicate that MCT injection in rats results in delayed but progressive endothelial injury and PH. Despite mild endothelial dysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related relaxation and elevation of ET-1 levels are associated with PH and RVH. Thus inhibition of NO production associated with elevated ET-1 levels may play an important role in the pathophysiology of MCT-induced PH.

摘要

目的

一氧化氮（NO）和内皮素 -1（ET -1）均与肺动脉高压（PH）的发病机制有关。因此，我们研究了在野百合碱（MCT）诱导的PH进展过程中，大鼠肺门肺动脉（PA）中与NO相关的舒张功能及ET -1水平。

方法

对单次皮下注射MCT（80 mg/kg）后1周和2周的大鼠进行研究。评估肺动脉压（PAP）、右心室肥厚（RVH）、PA中与NO相关的舒张功能及组织ET -1水平，并与对照组（C）进行比较。

结果

MCT注射后1周，PA对10⁻⁵ M二磷酸腺苷（ADP）、10⁻⁵ M A23187和10⁻⁵ M乙酰胆碱（ACh）的内皮（E）依赖性舒张以及组织ET -1水平均正常。该组大鼠未发生PH或RVH。MCT注射后2周，E依赖性舒张功能受损（ADP，7±3% 对比C组，62±5%；A23187，2±7% 对比C组，58±2%；ACh，33±7% 对比C组，86±2%；P<0.05），且ET -1水平升高（1925±244 pg/g湿重对比C组，469±59 pg/g湿重，P<0.05）。此外，出现了显著的PH和RVH（PAP 33±4 mmHg对比C组18±0.8 mmHg，P<0.05；RVH指数0.40±0.006对比C组，0.25±0.01，P<0.05）。用10 μM吲哚美辛、150 U/ml超氧化物歧化酶或300 μM L -精氨酸孵育未能恢复对ACh受损的舒张功能。在E完整的血管环中，MCT注射后1周对10⁻⁶ M硝酸甘油（GTN）的舒张功能受到抑制（72±2%对比C组，87±3%，P<0.05），2周时进一步受到抑制（39±4%）。在MCT组中，E去除的血管环对GTN的反应正常。

结论

这些结果表明，给大鼠注射MCT会导致延迟但进行性的内皮损伤和PH。尽管MCT注射后1周存在轻度内皮功能障碍，但与NO相关的舒张功能及ET -1水平正常。MCT注射后2周，E依赖性NO相关舒张功能的抑制及ET -1水平的升高与PH和RVH相关。因此，与升高的ET -1水平相关的NO生成抑制可能在MCT诱导的PH的病理生理学中起重要作用。