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Nitric oxide protects against pathological ventricular remodeling: reconsideration of the role of NO in the failing heart.

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 β-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 β-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 spatial confinement and localization of NOS isoforms. Studies in NOS1 and NOS3 null mice have demonstrated that by virtue of isoform-dependent localization of NO release and attendant divergent effects on SR and SL Ca2+ flux, each isoform exerts …