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 hypoxia-induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague-Dawley 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. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1β and IL-10. 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 molecule-1 (PECAM-1) 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 hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1β and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia-induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 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 PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH.
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Rong
R
Zhu
Geriatric Intensive Care Unit, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Li-Qing
LQ
Bi
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Su-Ling
SL
Wu
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Lan
L
Li
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Hui
H
Kong
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Wei-Ping
WP
Xie
Department of Respiratory Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Hong
H
Wang
Department of Respiratory Medicine, The Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China.
Zi-Li
ZL
Meng
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000032:analysis; D053583:Interleukin-1beta / Q000032:analysis; D054086:KATP Channels / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014132:Trachea / Q000473:pathology
D053583:Interleukin-1beta; D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011437:Propylamines; D016753:Interleukin-10; D052250:Nitric Oxide Synthase Type III