Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
PLoS One. 2012;7(9):e44485. doi: 10.1371/journal.pone.0044485. Epub 2012 Sep 7.
Most of the deaths among patients with severe pulmonary arterial hypertension (PAH) are caused by progressive right ventricular (RV) pathological remodeling, dysfunction, and failure. Nicorandil can inhibit the development of PAH by reducing pulmonary artery pressure and RV hypertrophy. However, whether nicorandil can inhibit apoptosis in RV cardiomyocytes and prevent RV remodeling has been unclear.
METHODOLOGY/PRINCIPAL FINDINGS: RV remodeling was induced in rats by intraperitoneal injection of monocrotaline (MCT). RV systolic pressure (RVSP) was measured at the end of each week after MCT injection. Blood samples were drawn for brain natriuretic peptide (BNP) ELISA analysis. The hearts were excised for histopathological, ultrastructural, immunohistochemical, and Western blotting analyses. The MCT-injected rats exhibited greater mortality and less weight gain and showed significantly increased RVSP and RV hypertrophy during the second week. These worsened during the third week. MCT injection for three weeks caused pathological RV remodeling, characterized by hypertrophy, fibrosis, dysfunction, and RV mitochondrial impairment, as indicated by increased levels of apoptosis. Nicorandil improved survival, weight gain, and RV function, ameliorated RV pressure overload, and prevented maladaptive RV remodeling in PAH rats. Nicorandil also reduced the number of apoptotic cardiomyocytes, with a concomitant increase in Bcl-2/Bax ratio. 5-hydroxydecanoate (5-HD) reversed these beneficial effects of nicorandil in MCT-injected rats.
CONCLUSIONS/SIGNIFICANCE: Nicorandil inhibits PAH-induced RV remodeling in rats not only by reducing RV pressure overload but also by inhibiting apoptosis in cardiomyocytes through the activation of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. The use of a mitoK(ATP) channel opener such as nicorandil for PAH-associated RV remodeling and dysfunction may represent a new therapeutic strategy for the amelioration of RV remodeling during the early stages of PAH.
大多数肺动脉高压（PAH）患者的死亡是由右心室（RV）进行性病理重塑、功能障碍和衰竭引起的。尼可地尔通过降低肺动脉压和 RV 肥厚来抑制 PAH 的发展。然而，尼可地尔是否能抑制 RV 心肌细胞凋亡，防止 RV 重塑尚不清楚。
方法/主要发现：腹腔注射野百合碱（MCT）诱导 RV 重塑。在 MCT 注射后每周末测量 RV 收缩压（RVSP）。采集血样进行脑钠肽（BNP）ELISA 分析。取出心脏进行组织病理学、超微结构、免疫组织化学和 Western blot 分析。MCT 注射大鼠死亡率较高，体重增长较少，第二周 RVSP 和 RV 肥厚明显增加，第三周加重。MCT 注射 3 周导致病理性 RV 重塑，表现为肥大、纤维化、功能障碍和 RV 线粒体损伤，凋亡水平升高。尼可地尔改善了 PAH 大鼠的生存、体重增加和 RV 功能，减轻了 RV 压力超负荷，并防止了 PAH 大鼠适应性 RV 重塑。尼可地尔还减少了凋亡心肌细胞的数量，同时 Bcl-2/Bax 比值增加。5-羟癸酸（5-HD）逆转了尼可地尔在 MCT 注射大鼠中的这些有益作用。
结论/意义：尼可地尔不仅通过降低 RV 压力超负荷来抑制 PAH 诱导的 RV 重塑，还通过激活线粒体 ATP 敏感性钾（mitoK（ATP））通道抑制心肌细胞凋亡。使用尼可地尔等 mitoK（ATP）通道开放剂可能为改善 PAH 早期 RV 重塑和功能障碍提供一种新的治疗策略。
