Nitric Oxide and Cardiac Function

Abstract

Abstract-Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology. (Circ Res. 2003;93:388-398.)Key Words: nitric oxide Ⅲ contractile function Ⅲ cardiomyocytes Ⅲ endothelium Ⅲ heart failure A s the prototypical endothelium-derived relaxing factor, nitric oxide (NO) is a primary determinant of blood vessel tone and thrombogenicity. Applied to heart tissue, these functions alone largely justify the growing interest for NO as a regulator of cardiac function. However, the recognition that all three isoforms of nitric oxide synthase (NOS) are expressed in cardiomyocytes themselves has raised several intriguing questions regarding the signaling role of NO in the heart.The modulatory effects of NO on contractile function are undoubtedly complex. [1][2][3][4] Perhaps this is expected when one considers the versatility of NO biochemistry, the multiplicity of its intracellular targets (with sometimes opposite contractile influences), as well as the diversity of its cellular sources within the myocardium. However, subcellular targeting of NO, driven in a stimulus-specific manner, ensures coordinate regulation of cardiac function. Mouse models genetically deficient or overexpressing one or several of the three NOS isoforms helped to clarify the role of endogenously produced NO (versus exogenous NO from pharmacologic sources) in normal or diseased hearts despite several unanswered questions. In the following paragraphs, we attempt to revisit the major paradigms on the influence of NO on several parameters of cardiac contraction with the hindsight of recent knowledge from genetic or molecular characterization of NOS regulation. Cellular Regulation of NOSTwo major posttranslational modes of regulation of en...

Synthetic Salusins as Cardiac Depressors in Rat

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Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

“…38,39 Furthermore, it has been suggested that eNOS-derived NO may exert beneficial effects by increasing the LV preload reserve and participate in maintaining the Frank-Starling response in the failing ventricle. [53][54][55] Moreover, recent studies have suggested that eNOS-derived NO production regulates myocardial oxygen consumption, 40,41 and increased eNO availability may thereby improve myocardial efficiency.…”

A novel method of measuring nitric-oxide-dependent fluorescence using 4,5-diaminofluorescein (DAF-2) in the isolated Langendorff-perfused rabbit heart

“…Apart from the well-established role of NO in vascular tone (Furchgott & Zawadzki, 1980), NO has been implicated to play a physiological role in heart rate (Herring et al, 2002) and contractile regulation (Cotton et al, 2001) as well having a pathological role in myocardial disease (Massion et al, 2003) and a protective role against ischaemia-reperfusion injury (Jones & Bolli, 2006). NO is synthesised from L-arginine by three distinct isoforms of nitric oxide synthase (NOS): neuronal (nNOS) or NOS 1, inducible (iNOS) or NOS 2 and endothelial (eNOS) or NOS 3, that can be found throughout the heart (Faber-Zuschratter & Wolf, 1994;Hecker et al, 1994;Rothe et al, 1998;Xu et al, 1999).…”