二氧化硫衍生物舒张大鼠离体主动脉血管环的效应及其机制研究

目的:探讨二氧化硫(sulfur dioxide, SO2)及其衍生物的舒张血管作用及其机制.方法:离体大鼠主动脉环灌流,应用去甲肾上腺素(noradrenaline, NE)预收缩主动脉环后,观察其对SO2供体--亚硫酸钠/亚硫酸氢钠混合液(Na2SO3/NaHSO3, 3:1物质的量比)的舒张反应;观察应用KATP通道阻断剂格列本脲和钙通道阻断剂尼卡地平对Na2SO3/NaHSO3血管效应的影响;观察应用内源性SO2生成酶抑制剂天冬氨酸异羟肟酸(hydroxamate,HDX)和Na2SO3/NaHSO3预孵育血管组织后NE缩血管效应的变化.结果:大鼠离体主动脉环对Na2SO3/NaHSO3呈浓度(0～12 mmol/L)依赖性的舒张反应,IC50值为(7.28±0.12) mmol/L,最大舒张率(Emax)为78.79%±3.24%.格列本脲(1×10^-6 mol/L)抑制低浓度Na2SO3/NaHSO3(≤4 mmol/L)的舒血管效应,而对高浓度(＞6 mmol/L)的舒血管效应无明显影响.经尼卡地平(1×10^-9 mol/L)预孵育的血管环对NE的收缩反应明显减弱,Na2SO3/NaHSO3则不能舒张该血管.反之,预先用HDX(1×10^-4 mol/L)孵育阻断内源性SO2生成后,血管环对NE的收缩反应增强[EC50从(6.48±0.84)×10^-7 mol/L降至(3.97±1.63)×10^-7 mol/L,P＜0.01];而用Na2SO3/NaHSO3预先孵育的血管对NE的收缩反应曲线右移[EC50从(6.48±0.84)×10^-7 mol/L升至(4.93±0.81)×10^-5 mol/L,P＜0.01].结论:SO2具有明显的舒张血管平滑肌作用,其作用机制与钙离子通道及KATP通道有关,推测机体内源性SO2具有血管功能调节意义.

Vasorelaxant effect of sulfur dioxide derivatives on isolated aortic rings of rats and its mechanisms

OBJECTIVE: To investigate the vasorelaxant effect of sulfur dioxide (SO(2)) on isolated aortic rings of rats in vitro and its relaxation mechanisms. METHODS: We perffused the isolated aortic rings of rats, and precontracted the rings with noradrenaline (NE), then observed the relaxant reactivity of SO(2) derivatives, mixture of sulfite and hydrogen sulfite [Na(2)SO(3)/NaHSO(3) 3:1(amount of substance)], to the aortic rings. Meanwhile, we studied the influence of glibenclamide and nicardipine, blockers of K(ATP) and L-calcium channels, on the vasorelaxant reactivity of SO(2) derivatives. We further incubated the aortic rings with hydroxamate (HDX), the inhibitor of SO(2) endogenous generating enzymes, and SO(2) derivatives (4 mmol/L) in vitro, then observed the contraction of the aortic rings to NE. RESULTS: Isolated aortic rings of rats exhibited relaxant reactivity to Na(2)SO(3)/NaHSO(3) (0-12 mmol/L) in a concentration-dependent manner. IC(50) of the relaxation curve was (7.28+/-0.12) mmol/Lìand Emax was 78.79%+/-3.24%. Glibenclamide (1x10(-6) mol/L) inhibited the vasorelaxation to low dose Na(2)SO(3)/NaHSO(3) (6 mmol/L). Nicardipine (1x10(-9) mol/L) could decrease the contraction of the rings to NE, and even could inhibit the relaxation of Na(2)SO(3)/NaHSO(3) almost completely. The inhibition of the endogenous SO(2) production with HDX (1x10(-4) mol/L), resulted in an increase in the contraction of rings. The contraction curve to NE shifted to the left, and IC(50) also changed from (6.48+/-0.84)x10(-7) mol/L to (3.97+/-1.63)x10(-7) mol/L (P<0.01). However, after the incubation of aortic rings with Na(2)SO(3)/NaHSO(3) (4 mmol/L), the contraction curve to NE shifted to the right, and IC(50) changed from (6.48+/-0.84)x10(-7) mol/L to (4.93+/-0.81)x10(-5) mol/L (P<0.01). CONCLUSION: SO(2) could relax vascular smooth muscles, and the mechanism might be associated with calcium channels and K(ATP) channels, suggesting that endogenous SO(2) could modulate the cardiovascular function.