Expression Of ATP-sensitive Potassium Channel Protein In Chronic Hypoxia Pulmonary Arterial Smooth Muscle Of Rats Induced By Pinacidil And Diazoxide

Objective: Chronic hypoxic pulmonary hypertension(CHPH) has been demonstrated to been the key event in the process chronic obstructive pulmonary disease(COPD) to chronic cor pulmonale. Previous study had found that the ATP-sensitive potassium channel opener Pinacidil(Pin) could prevent pulmonary hypertension in chronic hypoxic rats, and the mitochondrial ATP-sensitive potassium channel (MitoK_ATP) opener Diazoxide (DZ) could aggravate pulmonary hypertension, so the aim of this study was to investigate if any difference exists in protein levels of ATP-sensitive potassium channel (K_ATP) in pulmonary smooth muscles between chronic hypoxic and normal rats, and to examine if any changes of K_ATP channel protein level occurred after long-term Pinacidil and Diazoxide treatment.Methods: Sprague-Dawley rats were fed in hypoxic and normobaric environment (10±0.5% O₂, 6h·day^-1 and 6day·week^-1) to establish CHPAH model. Thirty-five male SD rats were randomly divided into control group (NS 5 ml/kg·d), hypoxic group (hypoxia + NS 5 ml/kg·d), Pin treated group (Pin 2.0 mg/kg·d via oral gavage + hypoxia), DZ treated group (DZ 1.5 mg/kg·d via oral gavage + hypoxia) and 5-HD+DZ treated group (5-HD 3.0 mg/kg·d, then DZ 1.5 mg/kg·d via oral gavage + hypoxia). 7 rats are included in each group. Four weeks later, the mean pulmonary arterial pressure (mPAP) was measured, then the rats were executed, and the stems of pulmonary artery were immediately dissected. Western-blot were performed to analyze the protein level of K_ATP channels in pulmonary main artery smooth muscles.Results: (1) The level of mPAP was significantly higher in the hypoxic group (36.41±2.08 mmHg) than those in control group (18.47±1.99 mmHg, P<0.05). Pinacidil treated group decreased the level of mPAP significantly (24.69±2.37 mmHg). While Diazoxide treated group increased the level of mPAP significantly (44.11±4.36 mmHg). The level of mPAP was significantly lower in the 5-HD + Diazoxide treated group (34.30±2.82 mmHg) than those in Diazoxide treated group. (2) The K_ATP channels were expressed in pulmonary main artery of rats. The protein level of SUR2B in the hypoxic group were significant lower than the control group (0.04±0.004 vs 0.12±0.01, P<0.05), Pinacidil treated group rats had higher expression levels than the hypoxic group (0.10±0.012 vs 0.04±0.004, P<0.05), Diazoxide treated group rats had lower expression levels than the hypoxic group (0.01±0.004 vs 0.04±0.004, P<0.05), and 5-HD + Diazoxide treated group rats had higher expression levels than the Diazoxide treated group (0.07±0.008 vs 0.01±0.004, P<0.05), and they also had higher expression levels than the hypoxic group (0.07±0.008 vs 0.04±0.004, P<0.05). Kir6.1 protein level did not show statically significant changes across the five groups.Conclusion: The expression of K_ATP channel was down-regulated in pulmonary artery of CHPAH rats, and this down-regulation was prevented by Pin in chronic hypoxic rats. While DZ could fartherly down-regulate the K_ATP channel expression. The results indicate that dysfunction of K_ATP channel and MitoK_ATP channel of pulmonary artery maybe contribute to the pathogenesis of chronic hypoxia pulmonary hypertension.