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When the heart sleeps… Is the vagus resetting the myocardial ‘redox clock’?

Cecilia Vecoli, Nazareno Paolocci
DOI: http://dx.doi.org/10.1093/cvr/cvn009 609-611 First published online: 14 January 2008

“…living in the very copper rigging and secular miracle of communication

untroubled by the dumb voltages flickering their miles, the night long

in the thousands of unheard messages”.

Thomas Pynchon, from The Crying of Lot 49 (1966)The Crying of Lot 49

Reactive oxygen species (ROS) are main actors in the evolving drama of congestive heart failure (CHF),1 a neuroendocrine disorder in which excess ROS signalling contributes to sympathetic efferent fibre hyperactivation.2 Enhanced sympathetic outflow favours arrhythmias, myocardial remodelling/dysfunction and premature death (Figure 1), thus having pathogenetic and prognostic meaning. However, the sympathetic ‘arm’ of the autonomic nervous system (ANS) acts not only as a ‘victim’ of ROS but also as an ‘executioner’ of further ROS-induced myocardial damage. Indeed, spill-over of catecholamines and other hypertrophic agents such as serotonin, angiotensin II, and endothelin-1 may amplify oxidative stress via their own enhanced catabolism and/or ROS-induced ROS release from mitochondria, triggering apoptosis and cell death. Yet, many unknowns still surround the ANS–ROS ‘bi-univocal’ relationship in CHF. One is the role of the parasympathetic (vagal) component. Vagal nerve stimulation (VNS) limits the frequency of lethal ventricular arrhythmias in dogs,3 and in rats it attenuates cardiac remodelling and improves survival.4 The mechanisms for the latter, however, remain elusive.

Figure 1

Schematic representation of the contribution of sympathetic efferent overflow, NO and reactive oxygen species (ROS) in the pathogenesis of congestive heart failure (CHF). Some of the possible sites for the intervention of vagal efferent/afferent fibres (and their mediators) to brake the effects of the ‘sympathetic-ROS axis’ on heart structure and function are also depicted.

In the current issue of Cardiovascular Research, Tsutsumi et al.5 show that VNS normalizes the in vivo rate of electron spin resonance (ESR) signal decay in infarcted mice with CHF. This shift is proportional to hydroxyl radical (OH) generation, which is typically altered in CHF models.6 Antioxidants such as Tiron or dimethylthiourea (superoxide and OH scavengers, respectively) mimicked the protective effect of VNS, further supporting the concept that VNS attenuates ROS production. This effect was inhibited by atropine sulphate, suggesting M2 muscarinic receptor involvement. But how did VNS-M2 drive abate excess ROS generation in these failing hearts? Here, the authors documented pre- and postjunctional cholinergic actions to suppress the ‘norepineprine (NE)–ROS axis’. In isolated cardiomyocytes, β-receptor-mediated ROS production was suppressed by co-incubation with acetylcholine (ACh). It is known that the ACh/M2 pathway can offset β-signalling at the myocyte level. Indeed, pertussis toxin-sensitive Gi/o protein coupled with M2 receptors counters adenylyl cyclase activity that is triggered by Gs protein activation due to β-agonism. In vivo VNS significantly reduced NE concentration in left ventricular interstitial fluid, likely through inhibition of sympathetic drive at the presynaptic level. Vagal activation of M2-receptors located at adrenergic nerve terminals is known to suppress norepinephrine (NE) release from sympathetic efferents.7 In analogy to ESR signal decay rate, NE content was reduced significantly only in CHF mice, hinting to a cause–effect ‘NE-to-ROS’ relationship.

In addition to these muscarinic mechanisms, VNS-induced myocardial redox changes might also involve nitric oxide (NO) since the NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) attenuated VNS-induced benefits. Cardiac cholinergic neurons also contain NOS and are therefore capable of releasing NO. Neuronal NO supports the release of ACh,8 so inhibition of NOS might affect ROS indirectly through a cholinergic mechanism. Further, NO can ‘quench’ ROS directly9 or may inhibit NADPH oxidase,10 a major source of ROS in experimental1 and human CHF.11 Here, VSN also attenuated NADPH oxidase activity. In CHF, angiotensin II type 1 receptors are up-regulated in critical relay stations that modulate sympathetic motor neuron activity, i.e. the rostral ventrolateral medulla (RVLM) or the nucleus tractus solitarius (NTS). This up-regulation leads to a NADPH oxidase-dependent rise in superoxide production.12 NO is a sympatho-inhibitory agent. It is possible that NO deficit at the central nervous system (CNS) level may render these neurons more excitable, thereby enhancing sympathetic discharge.2 A decreased gene expression of neuronal NOS (nNOS) in these structures occurs in failing hearts of rats and rabbits.2 A definitive and more detailed proof for NO involvement in these effects awaits further investigations. Finally, vagus-induced bradycardia may help to restore (or preserve) the myocardial antioxidant armamentarium via sustained reduction in myocardial oxygen consumption (‘indirect way’). Is the vagus putting a brake on the possible myocardial energy inefficiency due to chronic β-stimulation?

The present study poses a palette of new, intriguing questions. In CHF the ‘drive’ through vagal efferent fibres can be substantially limited, and reduced vagal control in CHF (at least on heart rate) is likely due to changes of presynaptic (ganglionic)13 and CNS function. Additionally, adrenergic signalling can inhibit ACh release by acting at postganglionic cardiac vagal nerve terminals.14 These relatively ‘silent’ vagal fibres may be less effective in opposing NE spillover and associated ROS activation as well, contributing to establish a highly oxidative environment in this syndrome. Why does VNS affect ROS only in CHF hearts and not in controls? One intriguing possibility is that if NO is a mediator of the antioxidant VNS properties, then NO could be more needed in CHF than in control because central NO modulation of sympathetic function in the latter is likely to be already optimal and oxidative stress is not a factor in control hearts. Along this line, control and CHF vagal fibres responded to stimulation with the same reduction in heart rate. Thus, different target tissues (i.e. nodal vs. contractile) responded differently rather than nerves. Could more prolonged, chronic VNS lead to up-regulation (via ACh or other mediators) of nNOS and eNOS protein expression and activity? ACh has been shown to activate eNOS and to favour L-arginine uptake.15 Another looming question would be: what happens to vagal redox influences in sleep apnoea or hypertension where sympathetic hyperactivation, oxidative stress, and cardiovascular risk coexist?

This study by Tsutsumi et al.5 suggests an intriguing new mechanism for increased ROS signalling in the failing heart, i.e. the interplay (and imbalance) between sympathetic and vagal fibres in governing the cardiac redox environment. CHF is a syndrome characterized by ‘miscommunication’, and like the creatures in The Crying of Lot 49, the failing myocytes become relatively indifferent to the overwhelming sympathetic messages. But in addition to this ‘copper rigging’ that works redundantly and inefficiently (contributing to creation of ‘oxidized’ and ‘rusty’ wiring and structures), it is possible that the vagal fibres are relatively unable to oppose such sympathetic ‘noise’, also via a mechanism that implies the maintenance of the antioxidant ‘reserve’.

Finally, the pacemaker of circadian rhythms is in the hypothalamus, and light is known to trigger sympathetic discharge and vagal suppression through the suprachiasmatic nucleus via melatonin.16 Conversely, sleeping time is characterized by a predominantly ‘parasympathetic’ form of activity, coupled to a decrease in sympathetic tone during REM sleep. In addition to slowing down vegetative functions (i.e. cardiac rhythm), can the night (dark) time serve to restore myocardial and ‘antioxidant’ reserve under vagal control? And how? In zebrafish, light,17 like exercise and stress in humans, induces the production of H2O2, and NADPH oxidase is a major source of H2O2. Are vagal fibres in humans able to suppress excess ROS ‘centrally’ and/or implement the antioxidant armamentarium?

Funding

C.V. is supported by Scuola Superiore S. Anna (Pisa, Italy). N.P. is the recipient of a Scientist Development Grant (American Heart Association) and supported by NIH (HL075265).

Acknowledgements

The authors are very thankful to Dr Donald B. Hoover for critically reviewing the manuscript.

Conflict of interest: none declared.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of the Cardiovascular Research or of the European Society of Cardiology.

References