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European Journal of Heart Failure 2001 3(5):527-534; doi:10.1016/S1388-9842(01)00163-5
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© 2001 European Society of Cardiology

Nitric oxide: not just a negative inotrope

David Sarkara,b,*, Patrick Vallanceb and Sian E. Hardinga

a Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine Dovehouse St, London SW3 6LY, UK
b Centre for Clinical Pharmacology, University College London London, UK

* Corresponding author. Tel.: +44-20-7352-8121, ext. 3313; fax: +44-20-7823-3392. E-mail address: d.sarkar{at}ucl.ac.uk (D. Sarkar)


   Abstract
Top
 Abstract
1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
Nitric oxide (NO) appears to play a role in modulating cardiac function in both health and disease. Early studies in isolated rodent cardiac myocytes demonstrated a depressant effect of NO supplied by NO donors (exogenous) as well as NO generated within myocytes (endogenous). There is increasing evidence for a functional NO generating system within the human myocardium, which appears upregulated in certain disease states. Induction of the high output nitric oxide synthase isoform (iNOS) has been demonstrated in the failing myocardium, though its functional significance remains unproven. More recently published data have contradicted the notion that NO acts solely as a negative inotrope demonstrating positive inotropy in both isolated rodent and human ventricular myocytes in response to a range of NO donors. Different NO donors have different NO release kinetics and generate a range of NO species (NO·, NO+ and NO–) which may interact at a number of subcellular targets. The observed response of any cardiac preparation to an NO donor represents the net effect of activation of different effector targets and may explain the contradictory reported effects of NO. To realise the therapeutic potential of NO will require specific targeting at a subcellular level.

Key Words: Nitric oxide • Myocardium • Nitric oxide synthase isoform

Received December 20, 2000; Revised February 28, 2001; Accepted April 26, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
The discovery of an endothelium-derived relaxing factor [1] and its subsequent identification as nitric oxide (NO) has led to extensive work characterising the vascular effect of this potent dilator (reviewed by Moncada and Higgs [2]). In addition to its actions on blood vessels, early studies suggested that physiological levels of NO could play a role modulating cardiac function both in health and disease. This review considers the evidence for the presence of a NO generating system within the myocardium and the importance of such a system as a determinant of cardiac function. The distinct effects of exogenous NO supplied by pharmacological NO donors are also considered together with the possible therapeutic opportunities.


   2. Synthesis of NO
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
Endogenous NO is formed by the sequential oxidation of L-arginine (Fig. 1). This process is catalysed by a family of nitric oxide synthases (NOS) that utilise NADPH and oxygen as co-substrates. The NOS isotypes are the products of separate genes and share 50–60% protein sequence homology [3].


Figure 1
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  		Fig. 1 NOS catalysed conversion of L-arginine to L-citrulline and NO via the intermediate NG-hydroxy-L-arginine. Both steps require NADPH, oxygen and tetrahydrobiopterin (BH4). (Adapted from Mayer and Werner [71]).

 
Three NOS isoforms have been identified and named after the site of their initial isolation. The neuronal (nNOS or type I) and endothelial (eNOS or type III) are constitutively expressed and synthesise NO in response to increased Ca2+. The high output third isoform (iNOS or type II) may be induced in selected tissues in response to a range of inflammatory mediators and its activity is functionally independent of Ca2+. It is not a normal constituent of healthy cells but is thought to be expressed in response to pro-inflammatory signals as part of an innate host defence mechanism [4].

Exposure of isolated rat or guinea-pig myocytes to NO either in the form of dissolved NO gas or as NO from a spontaneous donor such as sodium nitroprusside has been shown to cause a modest depression of contractile amplitude [5]. Furthermore, myocytes from rodent models of sepsis, which show increased NO synthesis, similarly demonstrated myocardial systolic depression which could be partially [6] or completely reversed [7–9] by inhibition of NO synthesis using N-monomethyl-L-arginine (L-NAME). These initial observations led to the widespread view that NO is a negative inotrope. The production of NO within the human myocardium was seen as a potentially important depressant factor that could play a role in cardiac failure.


   3. Sources of NO in the heart
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
In animals and humans, NO may be generated adjacent to myocytes by eNOS present in the vascular endothelium of myocardial capillaries and venules and in the endocardial lining [10,11]. In addition, eNOS expression has been detected within rodent myocardium [12,13] and human atrial [14] and ventricular myocytes [15,16]. Although eNOS may generate modest levels of NO, the greatest interest has centred on the presence of the high output inducible NOS isoform (iNOS) which may be expressed in the myocardium, endocardium or infiltrating cells during inflammation.


   4. Controversy surrounds iNOS
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
The notion that the negative inotropic effect of NO seen in animal models of sepsis or inflammation could be of pathological significance in humans was supported by initial reports of increased activity of Ca2+-independent NOS in the myocardium of patients with dilated cardiomyopathy, myocarditis and postpartum cardiomyopathy, but not in ischaemic or valvular heart disease [17,18]. It was suggested that iNOS induction might have a central role in the aetiology of inflammatory cardiomyopathies. Subsequent studies (Table 1) confirmed the presence of iNOS mRNA in the myocardium in dilated cardiomyopathy (DCM) [19–21] but also found it in association with advanced cardiac failure from a range of other causes including ischaemic heart disease [19,21–24], septic shock [25], valvular heart disease [19], transplant rejection [26] and HIV-related cardiomyopathy [27]. Only one study examined the link between iNOS expression and change in cardiac function. In a cohort of allograft transplant recipients, induction of iNOS was associated with systolic and diastolic dysfunction determined by echocardiography [26]. However, the association between iNOS induction and cardiac failure falls short of any clear causal relationship.


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  		Table 1 Presence of a functional NOS system in the human myocardium

 
Although many studies have found iNOS expression in the failing human heart this has not been a universal finding in cardiomyopathy [25,28] or sepsis [28]. Conversely, iNOS mRNA and protein have been detected in some apparently healthy hearts [19] (non-failing donor organs) in which iNOS expression would be unexpected. Furthermore, the presence of iNOS mRNA and protein cannot be assumed to reflect functional iNOS activity. In dedifferentiated human myocytes, stimulation with cytokines and lipopolysaccharide (LPS) resulted in induction of iNOS mRNA but not protein [29]. The same cells were capable of expressing other functional proteins in response to the same stimulus, indicating that protein expression was possible but that iNOS mRNA was not translated. In contrast, transfection with iNOS cDNA resulted in expression of both message and protein, suggesting that cultured human myocytes can express functional iNOS but often lack the capacity to do so when stimulated with cytokines. These problems in inducing iNOS in human myocytes have also been seen in other human tissues [30]. It is clear that human iNOS differs markedly from rodent iNOS. The findings also urge caution when iNOS mRNA is detected in samples from human hearts since this is no guarantee that iNOS protein would also have been present.


   5. Where might iNOS be expressed?
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
The limited number of studies that have demonstrated iNOS message and activity in myocardial homogenates could not identify in which cell type iNOS is expressed. In animal models of sepsis, iNOS appears within individual myocytes resulting in reduced contractile function. In the human myocardium iNOS activity has been localised to vascular endothelium and smooth muscle cells [24] as well as infiltrating macrophages [23]. However, in contrast to animal models of sepsis, isolated human myocytes from failing explanted hearts, mostly with ischaemic or dilated cardiomyopathy, did not show reversal of their contractile depression with the NOS inhibitor L-NAME [31]. This may reflect an absence of iNOS within human myocytes or an absence of a reversible tonic effect of NO. Thus, a central functional role for iNOS in human heart failure remains to be proven.


   6. Endothelial NOS
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
Since endothelial cells express eNOS constitutively it has been suggested that they may influence local myocardial function. Brutsaert et al. (1988) [32] were the first to report an effect of the endocardial endothelium on contractile function. In isolated muscle strips, removal of the endocardium produced a reduction in the force of contraction and twitch duration. This reduction appears to contradict the subsequent observation of NO as a negative inotrope. However, the authors suggested that the endocardium may generate a series of mediators of which NO is only one. The physiological relevance of these findings has been controversial. The endothelial monolayer of the endocardium is in close proximity to only a very small proportion of the total myocardium. Therefore, its ability to exert an effect through release of a short-lived mediator such as NO must be in doubt.

In contrast, the endothelial lining of the coronary microvasculature is a possible paracrine source, which is local to the majority of myocytes. The close proximity allows diffusion of oxygen and could be bridged by a similar small readily diffusible molecule such as NO. A small scale study of bicoronary infusion of substance P, an eNOS activator, reported a small drop in peak LV pressure in healthy human hearts and transplant recipients [33].

Lengthy discussion of the effect of NO on myocardial relaxation is beyond the scope of this article and has been recently reviewed [34,35]. However, in the absence of adrenergic stimulation, the main effect of NO on the heart appears to be on myocardial relaxation and ventricular distensibility [36,37] which may underlie its reported ability to augment the Frank–Starling response [38]. Direct measurement of NO synthesis within the myocardium, using microelectrodes, has added further weight to this notion by showing that NO concentrations vary during the contractile cycle, peaking in early systole [39].


   7. NO donors
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 
NO donors, as their name implies, are able to provide NO or related species when applied to biological systems and they have been employed as tools to investigate the effects of NO. However, their actions are more complex than simply releasing NO· and caution should be applied in equating the effect of exogenous NO with that produced endogenously. The clinical use of NO donors such as GTN stretches back over 100 years [40]. In recent years a number of newer classes of NO donors have become available including nitrosothiols (reviewed by Butler [41] and Al-Sa'doni [42]), nonoates (reviewed by Keefer [43,44]) and sydnonimines. S-nitrosoglutathione (GSNO), a nitrosothiol, has generated considerable clinical interest as a vasodilator and antiplatelet agent [45–49]. Many classes of NO donor generate a range of forms of nitrogen monoxide. In addition to the free radical form NO· the other redox states of NO+ or NO– may be generated, although NO+ does not exist as a free species but rather as a transferable group. The proportions of the different redox forms may vary depending on the local redox environment. Different NO species are capable of divergent interactions with other biomolecules. Thus, the actions of an NO donor within a tissue or cell depends on donor concentration, the release rate of NO, the redox state and the presence of metals and protein thiol. NO donors are not all the same and selection of a particular donor and the experimental system used may be crucial in the observed biological response. Nevertheless, NO donors have been of value in investigating certain actions of NO as well as having therapeutic potential for the treatment of cardiac disease.


   8. Effect of NO donors on contractile function
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
9. Targets of NO
 10. Conclusions
 References
 
In contrast to the early reports of a cGMP-mediated negative inotropic effect of NO, more recent studies have revealed both positive and negative effects of NO donors on basal (summarised in Table 2) and beta adrenergic stimulated contraction [50,51].


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  		Table 2 Summary of recent studies reporting positive inotropy in response to applied NO donors

 
Many reports implicate cGMP as the central mediator of the observed response and have demonstrated a biphasic response with only high concentrations of NO donor inducing a negative effect [50,53,57,59]. Direct measurement of cyclic nucleotides suggested that low concentrations of NO induce only modest rises in cGMP accompanied by elevation of cAMP, whilst high NO concentrations are associated with a greater increase in cGMP and a fall in cAMP. Within cardiomyocytes two forms of the cAMP degrading enzyme phosphodiestrase (PDE) have been identified. PDE2 is activated by cGMP whilst PDE3 is inhibited. Inhibition of PDE3 by cGMP has been suggested to mediate the NO-induced rise in cAMP and the subsequent activation of the L-type calcium channel which results in positive inotropy [51].

Other reports have shown negative [60] and positive inotropy of NO in a manner independent of cGMP [57,61]. In the latter study isolated guinea pig and human ventricular myocytes were exposed to the nitrosothiol GSNO, in the presence of low concentration of β-adrenergic agonist or to the fast releasing nonoate donor DEA/NO alone. At 10 µM concentration there was a substantial positive effect on contractile amplitude in both guinea-pig and human cells (Fig. 2). These effects were independent of cAMP and cGMP and may be mediated by a direct effect on the L-type Ca2+ channel.


Figure 2
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  		Fig. 2 Effect of GSNO (3x10–5 M, n=8) and DEA/NO (10–5 M, n=6) on isolated human myocytes. Cell contraction amplitude is represented as a percentage of resting cell length. The mean response to GSNO was a relative increase in contraction of 48% compared with isoprenaline alone (P<0.05). The response of guinea-pig myocytes to GSNO (10–5 M), in the presence of isoprenaline (3x10–10 M) is shown for comparison. The source of the 14 human cell preparations included ischaemic cardiomyopathy (6), congenital heart disease (2), dilated cardiomyopathy (2), rejected donor organ (1) and three preparations from biopsies taken from patients undergoing routine mitral valve replacement. Reprinted with permission from [61].

 

   9. Targets of NO
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
10. Conclusions
 References
 
It appears at first, difficult to reconcile the divergent observed actions of NO but further investigation of the possible targets of NO activity goes some way to explain the reported variability. Soluble guanylate cyclase (sGC) is considered a major receptor for NO [62]. It catalyses the conversion of guanosine 5'-triphosphate (GTP) to cyclic guanosine 3',5'-monophosphate (cGMP). Within the cardiovascular system the sGC signal transduction pathways play a central role in vascular tone, platelet adhesion and also to a lesser extent myocyte function. The binding of NO to the haem moiety of sGC results in enzyme activation by some 400-fold [63]. This elevates cGMP levels and subsequently there is transmission of the signal to the downstream transduction elements such as cGMP-dependent protein kinase (reviewed by Lehman et al. [64]), cGMP gated cation channels (reviewed by Seagate et al. [65]) and cGMP regulated phosphodiesterases [66,67]. The diversity of targets for this second messenger may cause diverse and even opposing actions in different cell and tissue types (targets summarised in Fig. 3). Thus, perhaps it is not surprising that effects of NO itself may be highly variable.


Figure 3
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  		Fig. 3 Summarizes the potential targets for NO in the cardiovascular system at an organ, cellular and subcellular level.

 
There are other less well-defined paths in myocytes for NO signal transduction that are independent of sGC. NO may act on mitochondria to inhibit cytochrome oxidase [68] and hence to inactivate the respiratory chain and ATP production. Modulation of myocardial energetics independent of cGMP, is likely to involve S-nitrosylation of thiols, binding of NO to haem-containing proteins or iron sulfur clusters and formation of nitrotyrosines. Cardiac sarcoplasmic reticulum calcium release channels (ryanodine receptor) have been shown to be subject to S-nitrosylation [69] which modifies their function (a reaction theoretically favoured by NO+). Caspase, a cysteine protease involved in apoptosis, may also be inhibited by S-nitrosylation of its active site cysteine, giving NO a role as an anti-apoptotic signal [70]. How NO preferentially activates one or other target is unclear and the observed response of a given preparation to NO, is probably the net effect of activation of a range of different effector targets.


   10. Conclusions
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
References
 
There is little evidence that endogenously produced NO in the healthy heart plays a significant role in directly modulating systolic cardiac function. The cyclic changes in NO levels, peaking in diastole, has led to the suggestion that it may have a physiological role in increasing diastolic compliance. In disease states (dilated cardiomyopathy, sepsis, transplant rejection) there is thought to be increased NO concentrations in the myocardium which may be due to iNOS induction within the myocytes as well as from infiltrating inflammatory cells but the situation in the human heart remains unclear. In sepsis the depressant effects of endogenous NO generation in animal tissues may be partially or completely reversed by NOS inhibition. However, in whole animals or humans, the effects on vascular tone may obscure any overall benefit to cardiac function.

Exogenous NO donors cause effects which do not necessarily mirror those of endogenous NO. The kinetics of NO release, the species of NO generated and the targets affected may differ markedly. Positive as well as negative inotropy may occur via mechanisms dependent and independent of sGC. These newly described effects may change attitudes towards the use of NO donors therapeutically, and to the role of endogenous nitrosothiols in normal cardiovascular function. If selective modulation of NO targets in the heart became a reality, drugs to increase cardiac contractility or alter myocardial oxygen consumption may emerge.


   Acknowledgements
 
Dr D. Sarkar is supported by a BHF Clinical Research Fellowship.


   References
Top
 Abstract
 1. Introduction
 2. Synthesis of NO
 3. Sources of NO...
 4. Controversy surrounds iNOS
 5. Where might iNOS...
 6. Endothelial NOS
 7. NO donors
 8. Effect of NO...
 9. Targets of NO
 10. Conclusions
 References
 

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