Effects of nitric oxide synthase inhibition on microvascular reactivity in septic mice.
Effects of nitric oxide synthase inhibition on microvascular reactivity in septic mice.
复制标题
一氧化氮合酶抑制对脓毒症小鼠微血管反应性的影响。
DOI：
10.1097/00024382-199910000-00003
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Parrillo,JE
中科院分区：
文献类型：
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作者：
Hollenberg,SM;Easington,CR;Osman,J;Broussard,M;Parrillo,JE
持续性血管扩张对血管加压药无效是感染性休克的特征。脓毒症诱导的细胞因子在血管系统内诱导一氧化氮合酶（NOS）是这种难治性血管舒张的主要介质之一。为了探讨脓毒症的血管舒张机制，我们在盲肠结扎和穿孔造成脓毒症的小鼠中，使用活体视频显微镜测量了局部灌注去甲肾上腺素的微血管收缩反应，并对比了局部灌注非选择性NOS抑制剂NG-甲基-L-精氨酸（L-NMMA）和选择性诱导型NOS（iNOS）抑制剂S-甲基-异噻唑啉（SMT）的作用。脓毒症小鼠对去甲肾上腺素的血管收缩作用的敏感性低于对照组（EC 50，产生半数最大反应的浓度为2.0+/-0.6 x 10-6 M vs. 7.9+/-2.2 x 10-8 M，P= 0.01）。局部SMT（100 [mu] M）选择性抑制诱导型iNOS可显著增加脓毒症小鼠的儿茶酚胺反应性，但不影响对照组的反应性（脓毒症组P= 0.0007，对照组P= 0.24）。局部L-NMMA的非选择性NOS抑制在脓毒症小鼠中产生了类似的儿茶酚胺反应性增加，但在对照组中没有（脓毒症组P= 0.001，对照组P= 0.56）。当过量（1 mM）的L-精氨酸，NOS的底物，被添加到灌流缓冲液沿着SMT和L-NMMA，小动脉对去甲肾上腺素的反应性降低到原来的值。这些实验表明，iNOS抑制在逆转败血症中降低的儿茶酚胺反应性方面与非选择性NOS抑制一样有效。这表明微血管激活的iNOS在低血压的病理生理学和降低血管加压素反应性在败血症中的一个至关重要的作用。
Persistent vasodilation refractory to vasopressor agents is characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines within the vasculature is one of the primary mediators of this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure microvascular vasoconstrictive responses to topical suffusion of norepinephrine in mice made septic by cecal ligation and puncture, and contrasted the effects of topical superfusion of the nonselective NOS inhibitor NG-methyl-L-arginine (L-NMMA) and the selective inducible NOS (iNOS) inhibitor S-methyl-isothiourea (SMT). Mice with sepsis were less sensitive to the vasoconstrictive effects of norepinephrine than controls (EC50, the concentration that produces half-maximal response 2.0+/-0.6 x 10-6 M vs. 7.9+/-2.2 x 10-8 M, P= 0.01). Selective inhibition of inducible iNOS with topical SMT (100 [mu] M) markedly increased catecholamine reactivity in mice with sepsis but did not affect reactivity in controls (P= 0.0007 for sepsis, P= 0.24 for controls). Nonselective NOS inhibition with topical L-NMMA produced a similar increase in catecholamine reactivity in mice with sepsis but not controls (P= 0.001 for sepsis, P= 0.56 for controls). When excess (1 mM) L-arginine, the substrate for NOS, was added to the superfusion buffer along with both SMT and L-NMMA, arteriolar responsiveness to norepinephrine was decreased to the original values. These experiments demonstrate that iNOS inhibition is as effective as nonselective NOS inhibition in reversing decreased catecholamine reactivity in sepsis. This suggests a crucial role for microvascular activation of iNOS in the pathophysiology of hypotension and decreased vasopressor responsiveness in sepsis.