The Effect Of Iptakalim On Hif-1α In Lung Tissue Of Rats With Chronic Hypoxic Pulmonary Hypertension

Background: Many respiratory diseases such as chronic pulmonary heart disease and chronic high altitude sicknes can lead to hypoxic pulmonary hypertension (HPH), HPH is an important pathophysiological stage. HPH involving both the altered smooth muscle proliferation and the enhanced hypoxic pulmonary vasoconstriction. It is well known that endothelin (ET), vascular endothelial growth factor(VEGF), erythropoietin (EPO) and nitric oxide (NO) can lead to HPH. Releases of endogenous vasoconstriction factors are involved in HPH during chronic hypoxia, such as ET-1 is a potent constrictor of pulmonary blood vessels, while NO is a potent vasodilator of pulmonary blood vessels.Hypoxia-induced pulmonary artery remodeling (PAR) is one of the important mechanisms for HPH, There are several agents involved in PAR, releases of endogenous vasoconstriction factors such as VEGF,EPO are involved in PAR during chronic hypoxia. Because of the releasing of EPO, the red blood cell were significantly increased which elevated blood viscosity ; increased resistance of blood flow,wall shear stress, leading to the enhanced hypoxic pulmonary vasoconstriction, thus, in turn to form HPH. In addition, the release of ET,NO,VEGF and EPO are closely associated with the production of Hypoxia inducible factor-1(HIF-1). Recently, potassium channels have been considered to be the most sensitive oxygen sensor of pulmonary arterial smooth muscle cells (PASMCs), there are at least three types of K⁺ channels: (1) voltage-gated K⁺ channels (Kv);(2) Ca²⁺-activated K+ channels ( Kca ) ;(3) ATP-sensitive K⁺ (KATP) channels. Among them, KATP channels are now thought to be the only compensation opened potassium channels in the response of ischemic and hypoxia.In normoxic condition, the KATP is always closed, In a hypoxic environment, the production of ADP,NDPs,MgNDPs and H+ increases, thus triggering activation of KATP which might play an important role in the protecting ischemic and hypoxia. The aim of the present study was to investigate the effect of Iptakalim,a novel ATP sensitive potassium channel opener(KATPCO),on HIF-1αin lung tissue of rats with chronic hypoxic pulmonary hypertension, and to explore the mechanisms underlying the effects of IPT on HPH.Objective: To investigate the effect of Iptakalim,a novel ATP sensitive potassium channel opener(KATPCO),on HIF-1αin lung tissue of rats with chronic hypoxic pulmonary hypertension.Methods: Thirty-six male Sprague-Dawley rats were randomly divided into three groups,the control group and HPH group were given 5.0 ml/kg.d 0.9% sodium chloride,ig;the IPT group were given 1.5 ml/kg.d IPT,ig.The HPH group and IPT group were exposed to normobaric environment of (10.0±0.5)% oxygen 8 hours a day,6 days a week, for 4 weeks. Reverse transcription polymerase chain reaction(RT-PCR) and Western-blot were used to assure the expression of HIF-1αmRNA and protein. Results Mean pulmonary arterial pressure (mPAP) and the weight ratio of right ventricle(RV) to left ventricle plus septum(LV+S) were much higher in the HPH group than those in the control group(P<0.01),and lower in the IPT group than those in the HPH group(P<0.01). Expressions of HIF-1αmRNA and protein in lung tissue of the HPH group were significantly higher compared with the control group(P<0.01), lower in the IPT group than them in the HPH group(P<0.01), and no difference between the control group and the IPT group.Conclusion: Iptakalim can effectively relieve HPH and maybe it is related to the inhibition of the mRNA and protein expression of HIF-1αin lung tissue.