Iptakalim attenuates hypoxia-induced pulmonary arterial hypertension in rats by endothelial function protection

The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxiainduced pulmonary arterial hypertension (PAH) rat model. Ninetysix SpragueDawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzymelinked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)1β and IL10. Immunohistochemical analysis for ED1+ monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule1 (PECAM1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxiainduced PAH rats. Iptakalim also prevented an increase in IL1β and a decrease in IL10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxiainduced PAH rats. Furthermore, iptakalim enhanced PECAM1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH.