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.
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【Role of nitric oxide and endothelin-1 in monocrotaline-induced pulmonary hypertension in rats.].
【一氧化氮和内皮素-1在单芥子碱诱导的大鼠肺动脉高压中的作用。】
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目的：一氧化氮（NO）和内皮素-1（ET-1）均与肺动脉高压（PH）的发病有关。因此，我们检查了单芥子碱（MCT）诱导的PH进程中大鼠肺门肺动脉（PA）中NO相关的松弛和ET-1水平。
方法：皮下注射MCT（80 mg / kg）1周和2周后，对大鼠进行研究。评价肺动脉压（PAP），右心室肥大（RVH），NO相关舒张和PA中组织ET-1的水平，并将其与对照组（C）进行比较。
结果：MCT后一周，内皮（E）依赖松弛至10（-5）M磷酸二腺苷（ADP），10（-5）M A23187和10（-5）M乙酰胆碱（ACh）和组织ET- PA中1个水平正常。该组中的大鼠未出现PH或RVH。 MCT后两周，E依赖的放松受到损害（ADP，7 /-3％VS. c，62 /-5％; A23187，2 /-7％vs. C，58 /-2％; ACh，33 /-相对于C为7％，86 /-2％; P <0.05）和ET-1水平升高（1925 /-244 pg / g wwt对C，469 /-59 pg / g wwt，P <0.05 ），此外，存在明显的PH和RVH（PAP 33 /-4 mmHg vs.C 18 /-0.8 mmHg，P <0.05; RVH指数0.40 /-0.006 vs.C，0.25 /-0.01，P <0.05） 。与10 microM消炎痛，150 U / ml超氧化物歧化酶或300 microM L-精氨酸一起孵育无法恢复ACh的受损松弛。在E型完整环中，MCT后1周抑制到10（-6）M三硝酸甘油酯（GTN）的松弛（72 /-2％vs. C，87 /-3％，P <0.05），并进一步抑制在2周时（39 /-4％）。在MCT组中，E剥脱环对GTN的反应是正常的。
结论：这些结果表明，在大鼠中进行MCT注射可导致延迟但进行性的内皮损伤和PH。尽管在MCT后1周出现了轻度的内皮功能障碍，但NO相关的舒张和ET-1水平是正常的。 MCT后2周，抑制E依赖的NO相关松弛和ET-1水平升高与PH和RVH有关。因此，抑制与NO-1升高相关的NO产生可能在MCT诱导的PH的病理生理中起重要作用。
方法：皮下注射MCT（80 mg / kg）1周和2周后，对大鼠进行研究。评价肺动脉压（PAP），右心室肥大（RVH），NO相关舒张和PA中组织ET-1的水平，并将其与对照组（C）进行比较。
结果：MCT后一周，内皮（E）依赖松弛至10（-5）M磷酸二腺苷（ADP），10（-5）M A23187和10（-5）M乙酰胆碱（ACh）和组织ET- PA中1个水平正常。该组中的大鼠未出现PH或RVH。 MCT后两周，E依赖的放松受到损害（ADP，7 /-3％VS. c，62 /-5％; A23187，2 /-7％vs. C，58 /-2％; ACh，33 /-相对于C为7％，86 /-2％; P <0.05）和ET-1水平升高（1925 /-244 pg / g wwt对C，469 /-59 pg / g wwt，P <0.05 ），此外，存在明显的PH和RVH（PAP 33 /-4 mmHg vs.C 18 /-0.8 mmHg，P <0.05; RVH指数0.40 /-0.006 vs.C，0.25 /-0.01，P <0.05） 。与10 microM消炎痛，150 U / ml超氧化物歧化酶或300 microM L-精氨酸一起孵育无法恢复ACh的受损松弛。在E型完整环中，MCT后1周抑制到10（-6）M三硝酸甘油酯（GTN）的松弛（72 /-2％vs. C，87 /-3％，P <0.05），并进一步抑制在2周时（39 /-4％）。在MCT组中，E剥脱环对GTN的反应是正常的。
结论：这些结果表明，在大鼠中进行MCT注射可导致延迟但进行性的内皮损伤和PH。尽管在MCT后1周出现了轻度的内皮功能障碍，但NO相关的舒张和ET-1水平是正常的。 MCT后2周，抑制E依赖的NO相关松弛和ET-1水平升高与PH和RVH有关。因此，抑制与NO-1升高相关的NO产生可能在MCT诱导的PH的病理生理中起重要作用。
