Seddon Mike, Shah Ajay M, Casadei Barbara
Department of Cardiology, Cardiovascular Division, King's College London, London, United Kingdom.
Cardiovasc Res. 2007 Jul 15;75(2):315-26. doi: 10.1016/j.cardiores.2007.04.031. Epub 2007 May 10.
Nitric oxide (NO) generated constitutively within the heart has long been known to influence myocardial function; however, the precise nature of these effects has been controversial--at least in part--because of the experimental use of non-isoform-selective inhibitors of NO synthases (NOS) and unwarranted extrapolation from results obtained with NO donors. Recent studies using NOS-selective inhibitors and genetically modified models are beginning to redress the balance. It is well established that agonist-stimulated release of NO from eNOS in the coronary endothelium exerts paracrine effects on cardiomyocytes, predominantly affecting the timing of relaxation as well as myocardial oxygen consumption. A significant recent advance has been the finding that both eNOS and nNOS are constitutively expressed in distinct subcellular locations within cardiomyocytes. The relative autocrine role of these isoforms in the cardiomyocyte remains to be fully clarified but evidence suggests that the autocrine effects of nNOS may include the modulation of basal inotropy and relaxation, beta-adrenergic responsiveness, and the force-frequency relationship. Myocardial eNOS, on the other hand, may be involved in mediating the inotropic response to sustained stretch. These effects may change significantly in the diseased heart where the expression, activity and/or coupling of NOS isoforms to downstream effectors may be altered. In this article, we review the current understanding of this important but complex field, focussing particularly on contractile function and on recent advances in knowledge regarding the autocrine functions of nNOS-derived NO.
长期以来，人们已知心脏内持续生成的一氧化氮（NO）会影响心肌功能；然而，这些作用的确切性质一直存在争议——至少部分如此——这是因为在实验中使用了非同工型选择性一氧化氮合酶（NOS）抑制剂，以及从使用NO供体获得的结果进行了不合理的推断。最近使用NOS选择性抑制剂和基因改造模型的研究开始纠正这种平衡。冠状动脉内皮中eNOS受激动剂刺激释放的NO对心肌细胞发挥旁分泌作用，主要影响舒张时间以及心肌耗氧量，这一点已得到充分证实。最近的一项重大进展是发现eNOS和nNOS在心肌细胞内不同的亚细胞位置组成性表达。这些同工型在心肌细胞中的相对自分泌作用仍有待充分阐明，但有证据表明，nNOS的自分泌作用可能包括调节基础心肌收缩力和舒张、β-肾上腺素能反应性以及力-频率关系。另一方面，心肌eNOS可能参与介导对持续牵张的变力反应。在患病心脏中，NOS同工型与下游效应器的表达、活性和/或偶联可能发生改变，这些作用可能会发生显著变化。在本文中，我们综述了对这一重要但复杂领域的当前认识，特别关注收缩功能以及关于nNOS衍生的NO自分泌功能的最新知识进展。
