BACKGROUND: Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV), and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. METHODS AND RESULTS: Coronary vascular response was assessed using microangiography with synchrotron radiation in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the non-selective endothelin-1 receptor antagonist (ERA), macitentan was also examined. Myocardial viability was determined in SuHx model rats, using ¹⁸F-FDG PET and MRI. Endothelium-dependent and -independent vasodilator responses were significantly attenuated in the medium and small arteries of severe PH rats. ERA treatment significantly improved RCA vascular function compared to the untreated group. ERA treatment improved both the decrease in ejection fraction and the increased glucose uptake, and reduced RV remodeling. In addition, the upregulation of inflammatory genes in the RV was almost suppressed by ERA treatment. CONCLUSION: We found impairment of vasodilator responses in the RCA of severe PH rat models. Endothelin-1 activation in the RCA plays a major role in impaired vascular function in PH rats and is partially restored by ERA treatment. Treatment of PH with ERA may improve RV function in part by indirectly attenuating right heart afterload and in part by associated improvements in right coronary endothelial function.

中文翻译：

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同步辐射显微血管造影评价重度肺动脉高压大鼠右冠血管功能障碍


背景：肺动脉高压（PH）导致右心室（RV）心脏肥大，并最终因心室后负荷持续升高而导致右心室衰竭。我们假设 PH 中与后负荷增加相关的 RV 机械应力会损害右冠状动脉 (RCA) 的血管舒张功能。方法和结果：在两个成熟的 PH 大鼠模型、注射野百合碱或联合暴露于慢性缺氧和 Su5416 血管内皮生长因子受体阻断（SuHx 模型）中，使用同步加速器辐射微血管造影评估冠状血管反应。在 SuHx 模型中，还检查了非选择性内皮素 1 受体拮抗剂 (ERA) 马西替坦治疗的效果。使用¹⁸ F-FDG PET 和 MRI 测定 SuHx 模型大鼠的心肌活力。严重PH大鼠的中动脉和小动脉中内皮依赖性和非依赖性血管舒张反应显着减弱。与未治疗组相比，ERA 治疗显着改善了 RCA 血管功能。 ERA 治疗改善了射血分数的降低和葡萄糖摄取的增加，并减少了 RV 重塑。此外，ERA 治疗几乎抑制了 RV 中炎症基因的上调。结论：我们发现严重 PH 大鼠模型的 RCA 中血管舒张反应受损。 RCA 中的内皮素-1 激活在 PH 大鼠血管功能受损中发挥着重要作用，并且可通过 ERA 治疗部分恢复。用 ERA 治疗 PH 可以改善右心室功能，部分是通过间接减轻右心后负荷，部分是通过相关改善右冠状动脉内皮功能。