Objective:To investigate the effects of nicorandil,a mitochondria adenosine triphosphate(ATP)-sensitive potassium channel opener(mitoKATPCO) on the development of hypoxic pulmonary hypertension(HPH) in rats. Methods: Forty rats were randomly divided into 4 groups(control group and three hypoxic groups including the simple hypoxic,nicorandil treatment as well as the nicorandil+5-hydroxydecanoate treatment group) with 10 rats each. The latter three hypoxic groups were placed into normobaric hypoxic chamber(8 h/day and 6 days/week). After 4 weeks,the mean pulmonary arterial pressure(mPAP),right ventricle/left ventricle and septum[RV/(LV+S)] were measured and the morphologic changes of small pulmonary arterial were detected by microscopes after hematoxylin-eosin staining. Western blot was performed to analyze the protein expression of proliferating cell nuclear antigen(PCNA). Results: Hypoxia alone significantly increased the mPAP,RV/(LV+S) as well as the protein expression of PCNA,the morphologic changes also indicated the significant proliferation and remodeling of the small pulmonary artery in the hypoxic group. The treatment with nicorandil significantly antagonized these changes,and the beneficial effects of nicorandil could be blocked by 5-HD. Conclusion: Nicorandil can significantly reduce the pulmonary artery pressure,antagonize the right ventricular hypertrophy as well as the proliferation and remodeling of the small pulmonary artery through activating the mitoKATP channel. It is a promising candidate for the treatment of HPH.