肺動脈高血壓是一種漸進式且致命性的疾病,升高的肺動脈壓以及肺部血管重新朔型可能會導至右心室肥大甚至右心衰竭,而這些因素都有可能增加病患的危險性及死亡率。其中Rho kinase 的過度表現很可能包含在其複雜的病理機轉當中,在此篇研究當中,將探討KMUP-1這個 cGMP 依賴性的 Rho-kinase 抑制劑在 monocrotaline ( MCT ) 所慢性誘導產生之肺高壓鼠中的血管舒張作用,並針對 KMUP-1 對於 MCT 所誘發的肺動脈高血壓之預防機轉作探討。首先以八週齡的雄性 wistar 鼠進行動物實驗,第一天將其腹腔注射單一劑量的 MCT ( 60 mg/kg ),二十一天後即可誘導其產生成熟之肺動脈高血壓 ( 此為病態組 )。而在給藥組方面,為了預防在注射 MCT 後病程的發展,從注射 MCT 後,第二天即開始每天舌下給予 KMUP-1 ( 2.5 mg/kg ) 直到第二十一天,結果顯示,預防性的給予 KMUP-1( 2.5 mg/kg/day )可以減少 MCT 所產生的肺動脈高壓症狀,而且並不會影響平均動脈壓以及心跳頻率,再者,於右心室/左心室加中隔之重量比例值 (RV/LV+S) 中也顯示 KMUP-1有效減少 MCT 所造成的右心室肥大現象。 在大鼠肺部的組織病理切片中亦發現 MCT 會造成肺動脈血管壁增生、肥大的情況,而 KMUP-1 對於 MCT 所造成的周邊肺動脈血管中層的增生現象有抑制效果,另外,以西方點墨法分析大鼠肺部組織的蛋白質表現,發現 MCT 會使 Rho kinase 過度表現, eNOS、sGC、PKG 表現降低,而 KMUP-1 會反轉上述這些表現。 在肺部組織的免疫組織染色實驗中,肺動脈內皮層的 eNOS 亦受MCT 影響而減少,此一現象也在 KMUP-1 的參與下而有所改善。由上述結果可知 KMUP-1 選擇性對肺動脈血管的舒張作用、減少肺動脈血管中層之厚度和減少右心肥大,以及不影響全身血壓的特性,是個非常值得繼續發展的藥物。
Pulmonary arterial hypertension (PAH) and vascular remodeling may cause right ventricular hypertrophy and failure, which increases morbidity and mortality of patients. PAH is a progressive and fatal disease, Rho-kinase expression may be substantially involved in the pathogenesis of PAH. In this study, we examined the pulmonary vasodilation effects of KMUP-1, a cGMP-dependent Rho-kinase inhibitor, in chronic monocrotaline (MCT)-treated rats. Here, we report the preventive effects of KMUP-1 on MCT-induced PAH. Eight-week-old adult Wistar rats were given a single intraperitoneal injection of monocrotaline (MCT, 60mg/kg) to cause PAH at 21 days. For prevention of disease worsening, sublingual administration of KMUP-1(2.5 mg/kg) caused a pulmonary selective vasodilation, decreased medial thickness of the peripheral pulmonary artery and right ventricular hypertrophy in chronically MCT-treated rats.Western blotting analysis demonstrated that endothelial nitric oxide synthase (eNOS) and soluble guanylyl cyclase (sGC) in lung tissue were markedly decreased in the MCT-treated rats, but it was protected from worsening by KMUP-1. In addition, MCT increased expression of Rho kinase (ROCK II) which plays an important role to induce smooth muscle contraction and vascular remodeling. Theses finding indicated that sublingual administration of KMUP-1 can protect from MCT-induced PAH, without affecting systemic artery pressure in rats.