Introduction

Nitric oxide (NO) is a multifaceted molecule which plays key roles in many biological situations [1]. Endothelial nitric oxide synthase (eNOS) is the major NOS isoform responsible for cardiovascular homeostasis. eNOS is a calmodulin-acti-vated enzyme which consists of an oxygenase and a reductase domain containing binding sites for a variety of cofactors that promote electron transfer from one domain to the other, leading ultimately to the conversion of l-arginine to citrulline and NO [2] (Fig. 11.1).

Fig. 11.1 Reciprocal regulation of the eNOS catalytic activity by caveolin (Cav) and calcium-bound calmodulin (CaM). eNOS is a two-domain enzyme consisting of a reductase domain containing binding sites for flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and an N-terminal oxygenase domain with binding sites for heme, L-arginine (Arg) and tetrahydrobiopterin (BH4). eNOS is active as

Fig. 11.1 Reciprocal regulation of the eNOS catalytic activity by caveolin (Cav) and calcium-bound calmodulin (CaM). eNOS is a two-domain enzyme consisting of a reductase domain containing binding sites for flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and an N-terminal oxygenase domain with binding sites for heme, L-arginine (Arg) and tetrahydrobiopterin (BH4). eNOS is active as a dimer: NADPH-derived electrons are transferred to the flavins and then to the heme (located on the vis-à-vis monomer) where O2 can be recruited and catalyzes NO synthesis from L-arginine. Caveolin interaction with the eNOS oxygenase domain stabilizes the complex and prevents L-arginine binding, whereas caveolin interaction with the reductase domain antagonizes CaM binding and slows down electron transfer to the oxygenase domain, thereby inhibiting NO production.

cardiac myocytes cardiac myocytes

Cardiac Myocyte

Fig. 11.2 The multiple roles of nitric oxide (NO) in the healthy heart. Endothelial cells in coronary arteries (as in other vascular beds) constitutively express endothelial nitric oxide synthase (eNOS) that regulates critical vascular functions such as contractility, permeability, leukocyte adhesion, platelet aggregation and angiogenesis through basal and stimulated NO production. In cardiac myocytes, both eNOS and nNOS are constitutively expressed and modulate key processes including excitation-contraction coupling, mito-chondrial respiration, and receptor-mediated autonomic stimulation.

Fig. 11.2 The multiple roles of nitric oxide (NO) in the healthy heart. Endothelial cells in coronary arteries (as in other vascular beds) constitutively express endothelial nitric oxide synthase (eNOS) that regulates critical vascular functions such as contractility, permeability, leukocyte adhesion, platelet aggregation and angiogenesis through basal and stimulated NO production. In cardiac myocytes, both eNOS and nNOS are constitutively expressed and modulate key processes including excitation-contraction coupling, mito-chondrial respiration, and receptor-mediated autonomic stimulation.

The principal source of NO within the normal myocardium is the endothelium of the coronary vasculature. Endothelial cells constitutively express the eNOS isoform, which generates NO in response to specific extracellular signals to regulate vascular smooth muscle tone and thrombogenicity, among other actions [3] (Fig. 11.2). In addition to coronary vascular (and endocardial) endothelium, both atrial and ventricular myocytes - including specialized pacemaker tissue - also express eNOS. Excitation-contraction coupling, modulation of autonomic signaling and mitochondrial respiration are more directly regulated by myocyte-pro-duced NO [4] (see Fig. 11.2). Amazingly, the same molecule, NO, has been involved in many cardiovascular diseases [5]. A shift from finely regulated NO production by eNOS (and neuronal NOS, also expressed in cardiac myocytes) to a deregulated NO production by the inducible NOS isoform (iNOS) is, indeed, associated with a variety of heart diseases. The extent of NO release (e.g., limited for the two constitutive NOS and in large excess for iNOS) is thought to account for the differential effects on cardiac function. Recognition of the threshold above which NO becomes toxic is, however, unclear and certainly appears elusive when considering, for instance, the potential benefits of nitrates - medications which deliver large amounts of NO. A safer way of addressing the question of cytotoxic versus protective effects of NO is to emphasize the qualitative characteristics of NO release. Consequently, the following paragraphs will emphasize, by a series of examples, the developing consensual view according to which (in nonpathological states at least) NO exerts its regulatory roles by being produced at the right time in the right place.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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