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(Circulation Research. 2007;100:1.)
© 2007 American Heart Association, Inc.

Editorials

Myocyte Nitroso-Redox Imbalance in Sepsis

NO Simple Answer

Dan E. Berkowitz

From the Department of Anesthesiology and Critical Care Medicine, and Biomedical Engineering, Johns Hopkins University School of Medicine.

Correspondence to Dan E. Berkowitz, Department of Anesthesiology and Critical Care Medicine, and Biomedical Engineering, Johns Hopkins University School of Medicine, Tower 711, 600N Wolfe St., Baltimore, MD 21287. E-mail dberkowi@bme.jhu.edu

Key Words: nitric oxide • S-nitrosylation • NOS3 overexpression • xanthine oxidase • reactive oxygen species (ROS) • myocyte

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Our initial understanding that the inhibition of inducible nitric oxide synthase (iNOS or NOS2) dependent NO production in cardiac myocytes would restore contractile function and improve outcome in septic shock failed.¹ This was, in part, because of our then lack of understanding of the complexity of NO signaling in the cardiovascular system in health and disease. The initial paradigm that NO acts as a diffusible molecule to depress cardiovascular function uniformly and diffusely has been replaced by a more sophisticated yet incomplete model of NO signaling. It calls for NO to act in very defined signaling domains, through distinct signal transduction mechanism, sub-serving focused physiologic functions.² It is now well established that NO and NO-related species are significant modulators of cardiac muscle excitation-contraction coupling and that these species affect a number of molecules and channels that coordinate this process.² It has been further established that mammalian cardiac myocytes express all 3 of the isoforms of nitric oxide synthase: endothelial (eNOS or NOS3), neuronal (nNOS or NOS1), and iNOS or NOS2. Furthermore what determines the modulatory effects (sometimes directionally opposite) with regard to physiologic function is not only the signal transduction mechanism, but the spatial confinement of the enzyme within the cardiac myocyte. For example, NOS3 is targeted to the sarcolemmal caveolae associated with the caveolar membrane protein caveolin 3. There, it is coupled through the ß-3 adrenergic³ and muscarinic receptor, gyuanylyl cyclase and the second messenger cGMP to negatively regulate L-type Ca²⁺ channel-dependent Ca²⁺ influx. It thus acts as . . . [Full Text of this Article]

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