Iptakalim is a new ATP-sensitive potassium （KATp） channel opener, and it inhibits the proliferation of pulmonary arterial smooth muscle cells （PASMCs） and pulmonary vascular remodeling. However, the underlying mec...Iptakalim is a new ATP-sensitive potassium （KATp） channel opener, and it inhibits the proliferation of pulmonary arterial smooth muscle cells （PASMCs） and pulmonary vascular remodeling. However, the underlying mechanism remains unclear. In the present study, we found that iptakalim significantly decreased pulmonary artery pressure, inhibited pulmonary ariery remodeling and PKC-α overexpression in chronic hypoxia in a rat pulmonary hypertension model. Iptakalim reduced hypoxia-induced expression of PKC-α, and abolished the effect of hypoxia on PASMC proliferation significantly in a dose-dependent manner in vitro. Moreover, these effects were abol- ished by glibenclamide, a selective KArp channel antagonist. These results indicate that iptakalim inhibits PASMC proliferation and pulmonary vascular remodeling induced by hypoxia through downregulating the expression of PKC-α. Iptakalim can serve as a novel promising treatment for hypoxic pulmonary hypertension.展开更多
Background Chronic hypoxia can cause pulmonary hypertension and pulmonary heart disease with high mortality.The signal transduction pathway of protein kinase C (PKC) plays an important role in chronic pulmonary hype...Background Chronic hypoxia can cause pulmonary hypertension and pulmonary heart disease with high mortality.The signal transduction pathway of protein kinase C (PKC) plays an important role in chronic pulmonary hypertension. So it is necessary to investigate the effect of PKC on voltage-gated potassium (K +) channels in pulmonary artery smooth muscle cells of rats exposed to chronic hypoxia. Methods Male Wistar rats were randomly divided into a control group (group A) and a chronic hypoxia group (group B). Group B received hypoxia [oxygen concentration (10±1)%] eight hours per day for four consecutive weeks. Single pulmonary artery smooth muscle cells were obtained using an acute enzyme separation method. Conventional whole cell patch clamp technique was used to record resting membrane potential,membrane capacitance and voltage-gated K + currents. The changes in voltage-gated K + currents before and after applying paramethoxyamphetamine (PMA) (500 nmol/L),an agonist of PKC,and PMA plus carbohydrate mixture of glucose,fructose and xylitol (GFX) (30 nmol/L),an inhibitor of PKC,were compared between the two groups. Results The resting membrane potential in group B was significantly lower than that of group A: -(29.0±4.8) mV (n=18) vs -(42.5±4.6) mV (n=35) ( P <0.01). But there was no change in membrane capacitance between the two groups: (17.9±4.6) pF (n=40) vs (19.7±5.8) pF (n=31) ( P >0.05). The voltage-gated K + currents were significantly inhibited by PMA in group A,and this effect was reversed by GFX. However,the voltage-gated K + currents in group B were not affected by PMA. Conclusions The resting membrane potential and voltage-gated K + currents in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia decreased significantly. It seems that PKC has different effects on the voltage-gated K + currents of pulmonary artery smooth muscle cells under different conditions.展开更多
基金supported by the National Natural Science Foundation of China (No.30971319)the "Six Talent Peak" Project of Jiangsu Province (No.08-B)the grant from Open Project Program of the Key Disciplines of the Public Health Department of Jiangsu Province (No. XK13_200902)
文摘Iptakalim is a new ATP-sensitive potassium （KATp） channel opener, and it inhibits the proliferation of pulmonary arterial smooth muscle cells （PASMCs） and pulmonary vascular remodeling. However, the underlying mechanism remains unclear. In the present study, we found that iptakalim significantly decreased pulmonary artery pressure, inhibited pulmonary ariery remodeling and PKC-α overexpression in chronic hypoxia in a rat pulmonary hypertension model. Iptakalim reduced hypoxia-induced expression of PKC-α, and abolished the effect of hypoxia on PASMC proliferation significantly in a dose-dependent manner in vitro. Moreover, these effects were abol- ished by glibenclamide, a selective KArp channel antagonist. These results indicate that iptakalim inhibits PASMC proliferation and pulmonary vascular remodeling induced by hypoxia through downregulating the expression of PKC-α. Iptakalim can serve as a novel promising treatment for hypoxic pulmonary hypertension.
基金ThisworkwassupportedbyagrantfromtheNationalNaturalScienceFoundationofChina (No 3 9970 3 3 2 )
文摘Background Chronic hypoxia can cause pulmonary hypertension and pulmonary heart disease with high mortality.The signal transduction pathway of protein kinase C (PKC) plays an important role in chronic pulmonary hypertension. So it is necessary to investigate the effect of PKC on voltage-gated potassium (K +) channels in pulmonary artery smooth muscle cells of rats exposed to chronic hypoxia. Methods Male Wistar rats were randomly divided into a control group (group A) and a chronic hypoxia group (group B). Group B received hypoxia [oxygen concentration (10±1)%] eight hours per day for four consecutive weeks. Single pulmonary artery smooth muscle cells were obtained using an acute enzyme separation method. Conventional whole cell patch clamp technique was used to record resting membrane potential,membrane capacitance and voltage-gated K + currents. The changes in voltage-gated K + currents before and after applying paramethoxyamphetamine (PMA) (500 nmol/L),an agonist of PKC,and PMA plus carbohydrate mixture of glucose,fructose and xylitol (GFX) (30 nmol/L),an inhibitor of PKC,were compared between the two groups. Results The resting membrane potential in group B was significantly lower than that of group A: -(29.0±4.8) mV (n=18) vs -(42.5±4.6) mV (n=35) ( P <0.01). But there was no change in membrane capacitance between the two groups: (17.9±4.6) pF (n=40) vs (19.7±5.8) pF (n=31) ( P >0.05). The voltage-gated K + currents were significantly inhibited by PMA in group A,and this effect was reversed by GFX. However,the voltage-gated K + currents in group B were not affected by PMA. Conclusions The resting membrane potential and voltage-gated K + currents in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia decreased significantly. It seems that PKC has different effects on the voltage-gated K + currents of pulmonary artery smooth muscle cells under different conditions.
