Pharmacologically augmented S-nitrosylated hemoglobin improves recovery from murine subarachnoid hemorrhage.
Pharmacologically augmented S-nitrosylated hemoglobin improves recovery from murine subarachnoid hemorrhage.
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DOI：
10.1161/strokeaha.110.600569
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发表时间：
2011-02
期刊：
影响因子：
8.3
通讯作者：
Warner DS
中科院分区：
文献类型：
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作者：
Sheng H;Reynolds JD;Auten RL;Demchenko IT;Piantadosi CA;Stamler JS;Warner DS
S-亚硝化血红蛋白(S-亚硝化血红蛋白)通过调节微血管血流量，参与氧向组织的输送。本研究验证了一种假说，即吸入亚硝酸乙酯增强S-亚硝酸化血红蛋白可改善实验性蛛网膜下腔出血后的预后。初步剂量研究发现，20ppm的亚硝酸乙酯浓度可使S亚硝化血红蛋白浓度增加4倍，而高铁血红蛋白没有增加。采用小鼠大脑前动脉血管内穿孔模型，分别在空气中或单独空气中注射20ppm亚硝酸乙酯72h，测定神经功能、脑血管内径、脑含水量、脑组织氧分压和实质红细胞流速。在出血后72小时，接触空气和亚硝酸乙酯的小鼠有相似大小的血液凝块。亚硝酸乙酯改善了神经学评分和旋转功能；减轻了SAH引起的同侧大脑前动脉、大脑中动脉和颈内动脉的收缩；并防止了同侧脑含水量的增加。吸入亚硝酸乙酯可增加同侧大脑皮质的红细胞流速和皮质组织的氧分压，但对全身血压无影响。靶向的S-亚硝化血红蛋白改善了结果参数，包括血管直径、组织血流量、皮质组织氧分压和神经功能。增加内源性PO2依赖的NO生物活性递送，选择性地扩张受损的脑血管，在治疗SAH方面具有重要的临床潜力。
S-nitrosylated hemoglobin (S-nitrosohemoglobin) has been implicated in the delivery of O2 to tissues through the regulation of microvascular blood flow. This study tested the hypothesis that enhancement of S-nitrosylated hemoglobin by ethyl nitrite inhalation improves outcome after experimental subarachnoid hemorrhage (SAH). A preliminary dosing study identified 20 ppm ethyl nitrite as a concentration that produced a 4-fold increase in S-nitrosylated hemoglobin concentration with no increase in methemoglobin. Mice were subjected to endovascular perforation of the right anterior cerebral artery and were treated with 20 ppm ethyl nitrite in air, or air alone for 72 hours, after which neurologic function, cerebral vessel diameter, brain water content, cortical tissue PO2, and parenchymal red blood cell flow velocity were measured. At 72 hours after hemorrhage, air- and ethyl nitrite– exposed mice had similarly sized blood clots. Ethyl nitrite improved neurologic score and rotarod performance; abated SAH-induced constrictions in the ipsilateral anterior, middle cerebral, and internal carotid arteries; and prevented an increase in ipsilateral brain water content. Ethyl nitrite inhalation increased red blood cell flow velocity and cortical tissue PO2 in the ipsilateral cortex with no effect on systemic blood pressure. Targeted S-nitrosylation of hemoglobin improved outcome parameters, including vessel diameter, tissue blood flow, cortical tissue PO2, and neurologic function in a murine SAH model. Augmenting endogenous PO2-dependent delivery of NO bioactivity to selectively dilate the compromised cerebral vasculature has significant clinical potential in the treatment of SAH.