Review article
Paracrine and autocrine effects of nitric oxide on myocardial function

https://doi.org/10.1016/S0163-7258(99)00072-8Get rights and content

Abstract

Complex paracrine interactions exist between endothelial cells and cardiac myocytes in the heart. Cardiac endothelial cells release (or metabolize) several diffusible agents (e.g., nitric oxide [NO], endothelin-1, angiotensin II, adenylpurines) that exert direct effects on myocyte function, independent of changes in coronary flow. Some of these mediators are also generated by cardiac myocytes, often under pathological conditions. This review focuses on the role of NO in this paracrine/autocrine pathway. NO modulates several aspects of “physiological” myocardial function (e.g., excitation-contraction coupling; myocardial relaxation; diastolic function; the Frank-Starling response; heart rate; β-adrenergic inotropic response; and myocardial energetics and substrate metabolism). The effects of NO are influenced by its cellular and enzymatic source, the amount generated, the presence of reactive oxygen species, interactions with neurohumoral and other stimuli, and the relative activation of cyclic GMP-dependent and -independent signal transduction pathways. The relative physiological importance of endothelium- and myocyte-derived NO remains to be established. In pathological situations (e.g., ischemia-reperfusion, left ventricular hypertrophy, heart failure, transplant vasculopathy and rejection, myocarditis), NO can potentially exert beneficial or deleterious effects. Beneficial effects of NO can result from endothelial-type nitric oxide synthase-derived NO or from spatially and temporally restricted expression of the inducible isoform, inducible-type nitric oxide synthase. Deleterious effects may result from (1) deficiency of NO or (2) excessive production, often inducible-type nitric oxide synthase-derived and usually with concurrent reactive oxygen species production and peroxynitrite formation. The balance between beneficial and deleterious effects of NO is of key importance with respect to its pathophysiological role.

Introduction

Over the last decade, it has become apparent that complex, paracrine interactions exist between endothelial cells and cardiac myocytes in the heart, analogous to the paracrine crosstalk between endothelial cells and vascular smooth muscle in blood vessels. Endothelial cell/cardiac myocyte interaction is now recognized to be important both physiologically and in disease states Brutsaert et al. 1998, Lewis & Shah 1997, Winegrad 1997. Several substances released or metabolized by cardiac endothelial cells have direct effects on cardiac myocyte function, including nitric oxide (NO), endothelin-1, prostanoids, natriuretic peptides, angiotensin II, kinins, reactive oxygen species (ROS), adenylpurines, and other factors so far characterized only in bioassay studies (reviewed by Lewis & Shah, 1997). Likewise, agents produced by cardiac myocytes, e.g., growth factors, can also affect endothelial function (Nishida et al., 1993). Some “endothelial” mediators (e.g., NO, endothelin-1) may be generated within cardiac myocytes themselves (as well as other cardiac cell types such as fibroblasts), often under pathological conditions, thereby exerting autocrine effects. In the present review, we focus on the role of NO in this paracrine/autocrine pathway.

Section snippets

Coronary vascular and endocardial endothelial cells

Two types of endothelial cells co-exist in the heart; namely, the endocardial endothelial monolayer of cells that lines the inner cavitary surfaces of the cardiac chambers and the vascular endothelial cells that line the coronary vessels. There are significant differences between these cell types, for example, with respect to embryological origin, their roles during cardiogenesis, cytoskeletal organization, electrophysiological properties, and the release of cardioactive mediators Brutsaert et

Nitric oxide synthase expression in the heart

NO is generated by a family of enzymes, the NO synthases (NOSs), which catalyze the conversion of the amino acid l-arginine to l-citrulline (for recent reviews, see Mayer & Hemmens 1997, Fleming & Busse 1999, Papapetropoulos et al. 1999). This reaction requires O2 and NADPH, as well as tetrahydrobiopterin (BH4). BH4 acts not only as a cofactor for NOS, but is thought to be required for maintenance of structural and functional stability of the enzyme. Three NOS isoforms have been identified,

Diversity of nitric oxide-dependent actions and signaling pathways

Since the first report of a direct effect of NO on myocardial contractile function in 1991 (Smith et al., 1991), an enormous number of studies have been published concerning its effects on the heart (recently reviewed by Kelly et al. 1996, Shah 1996, Lewis & Shah 1997). Multiple and sometimes contradictory actions have been reported. Apart from species and methodological differences, the response to NO in any given situation is likely to depend upon several factors, including (1) the cellular

Nitric oxide and the physiological regulation of myocardial contractile function

Many studies that have investigated the effects of NO on contractile function have focused on the modulation of systolic function, i.e., inotropic state. However, in studies where a full analysis of myocardial performance has been undertaken, NO has also been shown to exert significant effects on myocardial relaxation and diastolic properties, often even in the absence of changes in systolic function. Indeed, the original report of the effects of NO in the setting of an isolated papillary

Nitric oxide and myocardial energetics and metabolism

A series of studies by Hintze and colleagues have provided evidence for an influence of endothelium-derived NO on myocardial O2 consumption. These investigators first showed that an intravenous NOS inhibitor increased total body O2 consumption in conscious dogs, independent of changes in hemodynamics (Shen et al., 1994). In a follow-up study, they found that both exogenous NO and endogenously released NO could reversibly inhibit tissue O2 consumption in skeletal muscle slices (Shen et al., 1995)

Regulation of endothelial-type nitric oxide synthase expression and activation

Although eNOS is a constitutive protein in endothelial cells, it is recognized that its expression level can be altered by several stimuli. Most of the published data regarding the regulation of eNOS expression are derived from studies in large vessel endothelial cells. An increase in eNOS expression in cultured macrovascular endothelial cells in vitro was reported to occur in response to chronic fluid shear stress (Ranjan et al., 1995), exposure to transforming growth factor (TGF)-β (Inoue et

Induction of inducible-type nitric oxide synthase in myocardium: in vitro studies

Following the initial report by Schulz et al. (1992) of the induction of biochemical Ca2+-independent NOS activity in cardiac myocytes upon exposure to cytokines, numerous studies have demonstrated the induction of iNOS mRNA and protein in cardiac cells—not just cardiac myocytes, but also CMEC and endocardial endothelial cells, vascular smooth muscle, and infiltrating macrophages. Likewise, the expression of iNOS in the heart has been documented in several pathological situations associated

Role of nitric oxide in cardiac disease states in vivo: general considerations

The potential role of NO in the pathophysiology of cardiac dysfunction in various disease states has been the subject of considerable speculation, out of proportion to the actual data available. In many cases, this speculation has been based solely on in vitro findings, while in other cases, the only data has been a change in NOS expression/activity in vivo, with little or no investigation of functional consequences. Only relatively recently has it been appreciated that NO may influence cardiac

Role of nitric oxide in the myocardial depression of endotoxic shock

The initial suggestion that NO may contribute to the intrinsic myocardial depression that is a recognized feature of septic shock was made following the finding that Ca2+-independent NOS activity is expressed in cardiac myocytes isolated from rats injected with endotoxin (Schulz et al., 1992). These investigators found that Ca2+-independent NOS activity was maximal 6 hr after LPS injection. In subsequent studies on the hearts of endotoxin-injected rats, it was shown that iNOS mRNA was expressed

Nitric oxide and myocardial ischemia-reperfusion

NO (or the deficiency of NO) may influence several aspects of ischemia/reperfusion, via both direct effects on cardiac myocyte function and indirect effects due to changes in coronary perfusion. Furthermore, the effects of NO may vary according to the temporal phase.

Nitric oxide and ischemic preconditioning

Ischemic myocardial preconditioning is the phenomenon whereby one or more brief episodes of ischemia/reperfusion induce an increased tolerance to subsequent, more prolonged ischemia (Murry et al., 1986; recently reviewed by Yellon et al., 1998). This tolerance includes a reduction in myocardial infarct size (Murry et al., 1986), improved post-ischemic contractile function (reviewed by Bolli, 1996), and suppression of reperfusion-induced arrhythmia (e.g., Shiki & Hearse, 1987). Ischemic

Anti-hypertrophic effects of nitric oxide

Analogous to the potential for NO to inhibit vascular smooth muscle growth and proliferation, recent studies indicate that it can influence cardiac myocyte growth. In cultured neonatal rat cardiac myocytes, high dose glyceryl trinitrate decreased both phenylephrine-stimulated increases in protein content and the secretion of brain natriuretic peptide, a marker of hypertrophic phenotype (Harding et al., 1995). In the same study, the induction of iNOS by IL-1β reduced phenylephrine-stimulated

Role of inducible-type nitric oxide synthase expression?

There is considerable interest in the potential role of NO in the pathophysiology of cardiac dysfunction in heart failure. It has been suggested that excessive production of iNOS-derived NO (especially within the cardiac myocytes themselves) contributes to acute and chronic cardiac dysfunction in heart failure. This hypothesis is based mainly on studies reporting the presence of Ca2+-independent NOS activity de Belder et al. 1993, de Belder et al. 1995, Drexler et al. 1998 or of iNOS mRNA and

Allograft rejection

Good evidence implicates NO in the pathophysiology of cardiac transplant rejection. In rejecting allogeneic heart grafts in rats, the production of NO could be documented by EPR spectroscopy (Lancaster et al., 1992). iNOS induction was documented in cardiac myocytes, CMEC, and inflammatory cells in rejecting heterotopic abdominal cardiac transplants in rats (Yang et al., 1994). This was paralleled by nitrotyrosine immunostaining of myocytes and macrophages and by apoptosis of myocytes,

Myocarditis

The potential for beneficial, as well as deleterious, effects of iNOS (discussed in Section 8.2) is well illustrated by its roles in experimental viral and autoimmune myocarditis, respectively.

Conclusions

The data reviewed in this article indicate that NO produced by endothelial cells and cardiac myocytes may have an important role both in modulating physiological myocardial function and in the pathophysiology of several cardiac disease states. Aspects of physiological function that can be influenced by NO include excitation-contraction coupling, myocardial relaxation and diastolic function, the Frank-Starling response, heart rate, β-adrenergic inotropic response, and myocardial energetics and

Acknowledgements

We are very grateful to all our colleagues and collaborators who have contributed to the studies discussed here. A.M.S. holds the British Heart Foundation Chair of Cardiology at King's College London. P.A.M. was the recipient of a Medical Research Council Clinical Training Fellowship.

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