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Circulation Research. 2004;94:1155-1157
doi: 10.1161/01.RES.0000129569.07667.89
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(Circulation Research. 2004;94:1155.)
© 2004 American Heart Association, Inc.


Editorials

Nitric Oxide Protects Against Pathological Ventricular Remodeling

Reconsideration of the Role of NO in the Failing Heart

Sumanth D. Prabhu

From the Institute of Molecular Cardiology, Departments of Medicine and Physiology, and Biophysics, University of Louisville Health Sciences Center and Medical Service, Louisville Veterans Affairs Medical Center, Louisville, Ky.

Correspondence to Sumanth D. Prabhu, MD, Medicine/Cardiology, University of Louisville, ACB, Third Floor, 550 S Jackson St, Louisville, KY 40202. E-mail sprabhu@louisville.edu


Key Words: nitric oxide • nitric oxide synthase • ventricular remodeling • heart failure


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

Nitric oxide (NO) is generated by NO synthases (NOSs) that convert L-arginine to L-citrulline in the presence of molecular oxygen, nicotinamide-adenine dinucleotide phosphate, calmodulin, and several cofactors.1 Three NOS isoforms have been identified: NOS1 (neuronal NOS), NOS2 (inducible NOS), and NOS3 (endothelial NOS). The constitutive isoforms NOS1 and NOS3 display Ca2+-dependent calmodulin binding and are compartmentalized in cardiomyocytes, with NOS1 localizing to the ryanodine receptor of the sarcoplasmic reticulum (SR), and NOS3 localizing to the caveolae of the sarcolemma (SL) in close proximity to ß-adrenergic receptors and the L-type Ca2+-channel.2 NOS2 expression in cardiomyocytes requires induction in response to inflammatory cytokines or biological stress (eg, ischemia and reperfusion).3,4 NOS2 is expressed primarily in the cytosol, displays Ca2+-independent activity because of its high calmodulin-binding affinity, and has high capacity for generating NO.1,3,4

Modulation of cardiac function by NO is complex and multifaceted5,6 and is mediated by at least 2 mechanisms: activation of soluble guanylate cyclase with production of the second messenger cGMP and direct protein thiol nitrosylation. NO affects myocardial contraction in a dose-dependent biphasic fashion, with low NO concentrations (as occurs under normal, unstressed conditions) exerting positive inotropic effects and high concentrations exerting negative inotropic effects. Antecedent ß-adrenergic stimulation shifts the descending limb of this bimodal curve to the left, such that the negative inotropic effects become more prominent.5 NO hastens relaxation, shortens contraction duration, and improves diastolic distensibility,7,8 and also depresses mitochondrial respiration, thereby altering mechanoenergetic coupling.5,6,9 NO-mediated contractile effects are significantly impacted by . . . [Full Text of this Article]




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