Neuronal NO Synthase–Derived NO

Abstract

See related article, pages 242–249 Nitric oxide (NO) is generated by a family of NO synthases (NOSs) and is involved in a number of physiological and pathological processes in the cardiovascular system, most notably in the vasculature.1 The classic and, therefore, best-established action is its paracrine action in blood vessels, maintaining homeostasis, in that NO released from the endothelium reduces the tone of the vascular smooth muscle cells via activation of cGMP-dependent protein kinase (PKG).2 In the heart, 2 distinct types of NOSs, known as endothelial NOS (eNOS) and neuronal NOS (nNOS), are expressed in physiological settings (see elsewhere3,4 and references therein). Although both eNOS and nNOS are expressed in cardiomyocytes, they are localized to distinct subcellular compartments; that is, eNOS is localized to caveolae in the sarcolemma,5 whereas nNOS is localized predominantly to the sarcoplasmic reticulum (SR).6 In this issue of Circulation Research , Casadei and colleagues have refined our understanding of the role of nNOS-derived NO in the regulation of cardiac contractility, providing evidence that nNOS-derived NO accelerates ventricular relaxation via a cGMP/PKG-independent mechanism.7 Before discussing their novel findings, we would like to briefly summarize the mechanisms of cardiac muscle relaxation (Figure 1), based on the literature.8 Figure 1. Summary of players in myocardial relaxation. [Ca2+]i- and myofilament-based controls are documented. (The Ca2+ removal process via mitochondria is not shown for simplicity.) Proteins that are phosphorylated by PKA are marked in red. See the text for details. On stimulation of cardiomyocytes, Ca2+ enters the myocyte via sarcolemmal L-type Ca2+ channels and induces release of Ca2+ from the SR, resulting in Ca2+ binding to troponin (Tn)C and subsequent formation of cross-bridges, hence, the onset of contraction. Unlike in skeletal muscle, cardiac myofilaments …