Abstract: AIM: To investigate the changes of insulin sensitivity of pulmonary artery in rats with hypoxic pulmonary hypertension(HPH) and the influence of pioglitazone(PIO) treatment at different stages of the disease process and to analyze the role of insulin resistance in the development of HPH.METHODS: Twenty-eight male Sprague Dawley(SD) rats were randomly divided into four equal groups: normal group,HPH group,HPH 2nd week PIO group and HPH 4th week PIO group.Rats in HPH group,HPH 2nd week PIO group and HPH 4th week PIO group were exposed to low-pressure and low-oxygen condition in a self-modulating hypobaric and hypoxic cabin(air pressure 50 kPa,8 h/day for 4 weeks) to establish HPH in the animal model.HPH 2nd week PIO group and HPH 4th week PIO group were treated with PIO 10 mg/(kg·day) during the second and fourth weeks,respectively.After 4-week low-pressure and low-oxygen exposure,glucometer and ELISA method were used,respectively,to determinate the level of fasting blood glucose(FBG) and fasting serum insulin(FSI).Insulin resistance index(IRI) was then calculated.A microcatheter was inserted into the right ventricle and pulmonary artery through the right external jugular vein.Mean pulmonary arterial pressure(mPAP) and mean right ventricular pressure(mRVP) were measured.Right ventricle index(RVI) was then calculated.Changes of pulmonary vascular microstructure were observed through H/E staining.The main pulmonary artery was isolated from rat.Vasodilation effect of insulin on pulmonary artery rings pre-treated with phenephrine(PE) was investigated by in vitro perfusion technique.RESULTS: Compared with those in the control group,FBG,FSI,IRI,mPAP,RVP and RVI were significantly enhanced in HPH group(P<0.05).H/E staining showed hyperplasia in pulmonary artery smooth muscle and elastic fiber layer,wall thickening and vessel stenosis.Insulin-induced vasorelaxation reaction was significantly attenuated(P<0.05).Compared with those in the HPH group,FPG,FIN,IRI,mPAP,mRVP and RVI decreased in HPH 2nd week PIO group(P<0.05).Wall thickening and vessel stenosis were significantly reduced and insulin-induced vasorelaxation reaction was also significantly improved(P<0.05).However,compared with these changes,no significant difference was observed in HPH 4th week PIO group.CONCLUSION: Insulin resistance of pulmonary artery plays an important role in the development of hypoxia-induced pulmonary hypertension.Timely treatment is urgent.