Sub-cellular targeting of constitutive NOS in health and disease.

Constitutive nitric oxide synthases (NOSs) are ubiquitous enzymes that play a pivotal role in the regulation of myocardial function in health and disease. The discovery of both a neuronal NOS (nNOS) and an endothelial NOS (eNOS) isoform in the myocardium and the availability of genetically modified mice with selective eNOS or nNOS gene deletion have been of crucial importance for understanding the role of constitutive nitric oxide (NO) production in the myocardium. eNOS and nNOS are homologous in structure and utilize the same co-factors and substrates; however, they differ in their subcellular localization, regulation, and downstream signaling, all of which may account for their distinct effects on excitation-contraction coupling. In particular, eNOS-derived NO has been reported to increase left ventricular (LV) compliance, attenuate beta-adrenergic inotropy and enhance parasympathetic/muscarinic responses, and mediate the negative inotropic response to β3 adrenoreceptor stimulation via cGMP-dependent signaling. Conversely, nNOS-derived NO regulates basal myocardial inotropy and relaxation by inhibiting the sarcolemmal Ca(2+) current (I(Ca)) and promoting protein kinase A-dependent phospholamban (PLN) phosphorylation, independent of cGMP. By inhibiting the activity of myocardial oxidase systems, nNOS regulates the redox state of the myocardium and contributes to maintain eNOS "coupled" activity. After myocardial infarction, up-regulation of myocardial nNOS attenuates adverse remodeling and prevents arrhythmias whereas uncoupled eNOS activity in murine models of left ventricular pressure overload accelerates the progress towards heart failure. Here we review the evidence in support of the idea that NOS subcellular localization, mode of activation, and downstream signaling account for the diverse and highly specialized actions of NO in the heart. This article is part of a Special Issue entitled "Local Signaling in Myocytes".