Flögel U, Merx M W, Godecke A, Decking U K, Schrader J
Institute for Cardiovascular Physiology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):735-40. doi: 10.1073/pnas.98.2.735. Epub 2001 Jan 2.
The present study explored the role of myoglobin (Mb) in cardiac NO homeostasis and its functional relevance by employing isolated hearts of wild-type (WT) and myoglobin knockout mice. (1)H NMR spectroscopy was used to measure directly the conversion of oxygenated Mb (MbO(2)) to metmyoglobin (metMb) by reaction with NO. NO was applied intracoronarily (5 nM to 25 microM), or its endogenous production was stimulated with bradykinin (Bk; 10 nM to 2 microM). We found that infusion of authentic NO solutions dose-dependently (>/= 2.5 microM NO) increased metMb formation in WT hearts that was rapidly reversible on cessation of NO infusion. Likewise, Bk-induced release of NO was associated with significant metMb formation in the WT (>/=1 microM Bk). Hearts lacking Mb reacted more sensitively to infused NO in that vasodilatation and the cardiodepressant actions of NO were more pronounced. Similar results were obtained with Bk. The lower sensitivity of WT hearts to changes in NO concentration fits well with the hypothesis that in the presence of Mb, a continuous degradation of NO takes place by reaction of MbO(2) + NO to metMb + NO(3)(-), thereby effectively reducing cytosolic NO concentration. This breakdown protects myocytic cytochromes against transient rises in cytosolic NO. Regeneration of metMb by metMb reductase to Mb and subsequent association with O(2) leads to reformation of MbO(2) available for another NO degradation cycle. Our data indicate that this cycle is crucial in the breakdown of NO and substantially determines the dose-response curve of the NO effects on coronary blood flow and cardiac contractility.
本研究通过使用野生型（WT）和肌红蛋白基因敲除小鼠的离体心脏，探讨了肌红蛋白（Mb）在心脏一氧化氮（NO）稳态中的作用及其功能相关性。利用（1）H核磁共振波谱法直接测量氧合肌红蛋白（MbO₂）与NO反应转化为高铁肌红蛋白（metMb）的过程。通过冠状动脉内注射NO（5 nM至25 μM），或用缓激肽（Bk；10 nM至2 μM）刺激内源性NO的产生。我们发现，在WT心脏中，输注真实的NO溶液呈剂量依赖性（≥2.5 μM NO）增加metMb的形成，在停止输注NO后这种增加迅速可逆。同样，Bk诱导的NO释放与WT心脏中显著的metMb形成相关（≥1 μM Bk）。缺乏Mb的心脏对输注的NO反应更敏感，因为NO的血管舒张和心脏抑制作用更明显。Bk也得到了类似的结果。WT心脏对NO浓度变化的较低敏感性与以下假设非常吻合：在存在Mb的情况下，通过MbO₂ + NO反应生成metMb + NO₃⁻，NO会持续降解，从而有效降低细胞溶质NO浓度。这种分解保护心肌细胞色素免受细胞溶质NO的短暂升高影响。高铁肌红蛋白还原酶将metMb再生为Mb，随后与O₂结合导致可用于另一个NO降解循环的MbO₂重新形成。我们的数据表明，这个循环在NO的分解中至关重要，并在很大程度上决定了NO对冠状动脉血流和心脏收缩力影响的剂量反应曲线。
