败血症晚期NO/cGMP信号通路参与血管平滑肌细胞钙稳态失调

目的 :探讨败血症晚期 NO/ c GMP信号通路在血管平滑肌 (VSM)细胞钙稳态变化中的作用及其与血管低反应性的关系。方法 :采用盲肠结扎和穿孔法 (CL P)复制大鼠败血症模型 ,用离体血管灌流方法 ,测定内皮完整的主动脉环张力。结果 :CL P组动脉环对苯肾上腺素 (PE)和 KCl诱导的收缩反应量效曲线明显低于假手术组(SHAM) ;在无钙液中 ,CLP组动脉环由咖啡因诱导的收缩幅度与 SHAM组比无差别 (12 .3± 2 .0 vs 11.4± 2 .9,P>0 .0 5 ) ,而由 PE及随后加入的 Ca Cl2 所引起的收缩幅度则明显低于 SHAM组 (71.4± 9.1vs 2 8.6± 4 .9,2 70 .0±32 .3vs 15 7.2± 2 6 .4 ,P均 <0 .0 5 ) ;CLP组动脉环的钙浓度 -收缩曲线比 SHAM组明显右移 ,最大反应压低 ;经诱导型一氧化氮合酶抑制剂氨基胍和一氧化氮敏感的鸟苷酸环化酶抑制剂 ODQ预处理后 ,CL P组动脉环的收缩能力均可恢复或超过 SHAM组的水平。结论 :败血症晚期 NO/ c GMP信号通路 ,可能通过抑制 VSM中由受体操纵性 Ca2 + 通道和电压调控的 Ca2 + 通道介导的胞外 Ca2 + 内流 ,抑制 VSM中 IP3敏感的内钙释放 ,以及降低 VSM的收缩蛋白对 Ca2 + 的敏感性 ,从而导致 VSM低反应性的形成。

NO/cGMP signal pathway involved in the disturbance of calcium homeostasis in vascular smooth muscle during the late phase of sepsis

Objective: To evaluate the alterations in calcium metabolism of the vascular smooth muscle of rat thoracic aorta in the late phase of sepsis and to investigate the involvement of nitric oxide (NO)/cyclic-GMP (cGMP) signal transduction pathway in the sepsis-induced vascular hyporeactivity. Methods: Male Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). Eighteen hours post CLP,rat aortic rings were removed for measurement of contractile responses to vasoconstrictors by using organ bath technique. Results: In endothelium intact aortic rings from CLP rats,concentration-contraction curves to phenylephrine (PE) and high KCl were significantly decreased when compared with those from control rats. The transient contraction induced by PE in calcium-free Krebs solution and the concentration-dependent contraction to CaCl 2 in KCl-depola-rized medium were also markedly reduced. The hyporeactivity to vasoconstrictors was completely reversed by pretreatment either with aminoguanidine (AMG),a selective inducible nitric oxide synthase inhibitor,or with 1Hoxadiazoloquininoxalin-1-one (ODQ),an inhibitor of NO-sensitive guanylyl cyclase. Conclusion: A generalized impairment in calcium handling in vascular smooth muscle,including the calcium influx through the voltage-operated and receptor-operated channels and calcium release from intracellular calcium stores,is involved in vascular hyporeactivity during the late phase of sepsis. The NO/cGMP signal transduction pathway might be involved in this defect in vascular smooth muscle.