Sodium nitrite therapy attenuates the hypertensive effects of HBOC-201 via nitrite reduction.
Sodium nitrite therapy attenuates the hypertensive effects of HBOC-201 via nitrite reduction.
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亚硝酸钠疗法通过还原亚硝酸盐来减弱 HBOC-201 的高血压作用。
DOI：
10.1042/bj20090735
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
Patel,RakeshP
中科院分区：
文献类型：
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作者：
Rodriguez,Cilina;Vitturi,DarioA;He,Jin;Vandromme,Marianne;Brandon,Angela;Hutchings,Anne;Rue3rd,LoringW;Kerby,JeffreyD;Patel,RakeshP
继发于NO清除的高血压仍然是使用HBOC（基于血红蛋白的氧载体）的限制。最近的研究表明，亚硝酸盐还原为NO的脱氧血红蛋白支持NO信号。在本研究中，我们使用HBOC-201（Biopure）（一种牛交联低氧亲和力血红蛋白）测试了亚硝酸盐是否会减弱HBOC介导的高血压。与未修饰的血红蛋白类似，脱氧HBOC-201将亚硝酸盐还原为NO，其速率与脱氧程度成正比。HBOC-201依赖性亚硝酸盐还原的功能重要性使用离体主动脉环和创伤、出血和复苏的小鼠模型来证明。在前者，HBOC-201抑制NO供体和亚硝酸盐依赖性血管舒张时，氧合。然而，脱氧HBOC-201未能影响亚硝酸盐依赖性血管舒张，但仍抑制NO供体依赖性血管舒张，这与脱氧HBOC-201还原亚硝酸盐对抗NO清除的模型一致。最后，在创伤和出血后使用HBOC-201进行复苏，导致轻度高血压（约5-10 mmHg）。在HBOC-201复苏开始时给予单次推注亚硝酸盐（30-100 nmol）可预防高血压。亚硝酸盐对LR（乳酸林格氏液）复苏期间的平均动脉压没有影响，表明亚硝酸盐-HBOC反应在减弱HBOC介导的高血压中的作用。总之，这些数据支持亚硝酸盐可用作预防HBOC依赖性高血压的辅助治疗的概念。
Hypertension secondary to scavenging of NO remains a limitation in the use of HBOCs (haemoglobin-based oxygen carriers). Recent studies suggest that nitrite reduction to NO by deoxyhaemoglobin supports NO signalling. In the present study we tested whether nitrite would attenuate HBOC-mediated hypertension using HBOC-201 (Biopure), a bovine cross-linked, low-oxygen-affinity haemoglobin. In a similar way to unmodified haemoglobin, deoxygenated HBOC-201 reduced nitrite to NO with rates directly proportional to the extent of deoxygenation. The functional importance of HBOC-201-dependent nitrite reduction was demonstrated using isolated aortic rings and a murine model of trauma, haemorrhage and resuscitation. In the former, HBOC-201 inhibited NO-donor and nitrite-dependent vasodilation when oxygenated. However, deoxygenated HBOC-201 failed to affect nitrite-dependent vasodilation but still inhibited NO-donor dependent vasodilation, consistent with a model in which nitrite-reduction by deoxyHBOC-201 counters NO scavenging. Finally, resuscitation using HBOC-201, after trauma and haemorrhage, resulted in mild hypertension (~5–10 mmHg). Administration of a single bolus nitrite (30–100 nmol) at the onset of HBOC-201 resuscitation prevented hypertension. Nitrite had no effect on mean arterial pressure during resuscitation with LR (lactated Ringer's solution), suggesting a role for nitrite–HBOC reactions in attenuating HBOC-mediated hypertension. Taken together these data support the concept that nitrite can be used as an adjunct therapy to prevent HBOC-dependent hypertension.