Modulation of the NO/cGMP pathway reduces the vasoconstriction induced by acellular and PEGylated haemoglobin
Modulation of the NO/cGMP pathway reduces the vasoconstriction induced by acellular and PEGylated haemoglobin
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DOI：
10.1016/j.bbapap.2007.12.011
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发表时间：
2008-10-01
影响因子：
3.2
通讯作者：
Samaja, Michele
中科院分区：
文献类型：
--
作者：
Caretti, Anna;Fantacci, Monica;Samaja, Michele
NO/cGMP途径的激活调节血管收缩，从而调节血管收缩，这是无细胞血红蛋白(Hb)用作血液替代品的主要障碍，尽管与5-kDa马来酰亚胺(5-kDa)聚乙二醇偶联物(PEG)在体内降低了血管收缩。我们的目的是评估最近开发的一种聚乙二醇化的Hb(脱氧-PEGHb)和对NO/cGMP途径的操纵如何能够调节离体大鼠心脏的血管收缩。心脏用含氧Krebs-Henseleit(15ml/min)灌流，同时监测冠脉压(CPP)，在不改变流量的情况下，注射50 NM去甲肾上腺素后1min给予1mM Hb或Deoxy-PEGHb。与Hb相比，脱氧PEGHb引起的血管收缩作用更弱。尽管聚乙二醇的存在有助于血管收缩，但脱氧聚乙二醇乙二醇酯并不含有明显的游离聚乙二醇量。而用0.2mM L-NAME减少血管内皮细胞NO释放则增加血管收缩，用其杂环化合物取消Hb对NO的清除几乎完全钝化血管收缩作用。此外，通过用0.02 mM西地那非抑制磷酸二酯酶-5来维持细胞内循环GMP，能够控制Hb诱导的血管收缩。我们的结论是，尽管聚乙二醇化血红蛋白是一种可能的方法来限制血红蛋白诱导的血管收缩，但操纵NO/cGMP通路可能提供一种有效的方法来绕过这一问题。(C)2008爱思唯尔B.V.保留所有权利。
Activation of the NO/cGMP pathway modulates smooth muscle cells relaxation and hence vasoconstriction, a major hindrance for the use of cell-free haemoglobin (Hb) as blood substitute, despite conjugation with 5-kDa maleimide poly(ethylene)-glycol (PEG) reduces vasoconstriction in vivo. We aimed at assessing how a recently developed PEGylated-Hb (Deoxy-PEGHb) and manipulation of the NO/cGMP pathway enable modulation of vasoconstriction in isolated rat hearts. Hearts were Langendorff-perfused with oxygenated Krebs-Henseleit (15 ml/min) while monitoring the coronary pressure (CPP) after injection (1 min) of 50 nM norepinephrine followed by a 1 mu M Hb or Deoxy-PEGHb bolus, without altering the flow. Deoxy-PEGHb induced less vasoconstriction than Hb. Although the presence of PEG could contribute to vasoconstriction, Deoxy-PEGHb did not contain appreciable amounts of free PEG. Whereas reducing endothelial NO release by 0.2 MM L-NAME increased vasoconstriction, abolishing NO scavenging by Hb using its cyanomet derivative almost completely blunted it. Furthermore, maintaining intracellular cyclic GMP by inhibiting phosphodiesterase-5 with 0.02 mM sildenafil enabled control of Hb-induced vasoconstriction. We conclude that, although PEG-Hb represents a possible approach to limit Hb-induced vasoconstriction, manipulating the NO/cGMP pathway may provide a powerful way to circumvent this problem. (C) 2008 Elsevier B.V. All rights reserved.