Michelakis Evangelos D
University of Alberta Hospitals, Walter C McKenzie Health Sciences Centre, Edmonton, Canada.
Heart Fail Rev. 2003 Jan;8(1):5-21. doi: 10.1023/a:1022150819223.
Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature leading to vasoconstriction and remodeling of the pulmonary arteries. The resulting increase in the right ventricular afterload leads to right ventricular failure and death. The treatment options are limited, expensive and associated with significant side effects. The nitric oxide (NO) pathway in the pulmonary circulation provides several targets for the development of new therapies for this disease. However, the NO pathway is modulated at multiple levels including transcription and expression of the NO synthase gene, regulation of the NO synthase activity, regulation of the production of cyclic guanomonophosphate (cGMP) by phosphodiesterases, postsynthetic oxidation of NO, etc. This makes the study of the role of the NO pathway very difficult, unless one uses multiple complementary techniques. Furthermore, there are significant differences between the pulmonary and the systemic circulation which make extrapolation of data from one circulation to the other very difficult. In addition, the role of NO in the development of pulmonary hypertension varies among different models of the disease. This paper reviews the role of the NO pathway in both the healthy and diseased pulmonary circulation and in several animal models and human forms of the disease. It focuses on the role of recent therapies that target the NO pathway, including L-Arginine, inhaled NO, the phosphodiesterase inhibitor sildenafil and gene therapy.
肺动脉高压（PAH）是一种肺血管疾病，可导致肺血管收缩和肺动脉重塑。由此导致的右心室后负荷增加会引发右心室衰竭并导致死亡。治疗选择有限、费用高昂且伴有显著的副作用。肺循环中的一氧化氮（NO）途径为开发针对该疾病的新疗法提供了多个靶点。然而，NO途径在多个水平受到调节，包括NO合酶基因的转录和表达、NO合酶活性的调节、磷酸二酯酶对环磷酸鸟苷（cGMP）生成的调节、NO的合成后氧化等。这使得研究NO途径的作用非常困难，除非使用多种互补技术。此外，肺循环和体循环之间存在显著差异，这使得将数据从一种循环外推到另一种循环非常困难。此外，NO在肺动脉高压发展中的作用在该疾病的不同模型中有所不同。本文综述了NO途径在健康和患病肺循环以及几种动物模型和人类疾病形式中的作用。它重点关注了针对NO途径的近期疗法的作用，包括L-精氨酸、吸入性NO、磷酸二酯酶抑制剂西地那非和基因治疗。
