Clin Auton Res (2004) 14 : 6–8DOI 10.1007/s10286-004-0157-3 EDITORIAL

Edward J. F. Danson Is there anything nitroglycerin treatment can’t do?

Impaired cardiac parasympathetic regulation and en-hanced sympathetic activity characterize cardiac dis-ease states and are well-established independent predic-tors of mortality in patients with myocardial infarctionor heart failure [5, 10]. So far, attempts to reverse this sit-uation therapeutically have failed, largely because so lit-tle is known of the underlying causes.

The nitric oxide (NO) signaling system has long beenspeculated to be involved in shifting autonomic balancein the heart in favor of a high vagal tone by accentuatingcholinergic signaling, whilst attenuating beta-adrener-gic responsiveness [12]. Although this theory remainshighly controversial within the heart itself, most evi-dence supports the paradigm presynaptically within theheart’s autonomic nerve supply [15]. Furthermore, neu-ronal NO synthase (nNOS) appears to be upregulated inthese nerves in response to cardiac stress (chronic exer-cise [6] or myocardial infarction [17]) leading to en-hanced parasympathetic control over heart rate. Such amechanism may represent an important protective re-sponse to counteract the damaging effects of high levelsof sympathetic discharge.

A new clinical study by Buch and co-workers [1] hastargeted this response with transdermal glyceryl trini-trate (GTN) patches, widely used in the treatment ofangina, which release NO directly through the skin. Theobjective of this study was to enhance cardiac vagal con-trol in patients with heart failure (HF). Although theprocess of treatment in this case was scientifically soundand rigorous, the GTN patch appears to have failed to in-crease necessary indices of vagal tone.

Using different drugs, the authors themselves (as wellas others) have shown that the high frequency compo-nent of heart rate variability (HRV, in this case the cho-sen index of cardiac vagal control) can be successfullymanipulated by NO-targeted therapy. The NO donor,sodium nitroprusside [2] or the NOS substrate, L-argi-nine [4] can increase HRV, whilst the constitutive NOSinhibitor, L-NMMA [2] can decrease it compared to ap-propriate control substances in healthy human volun-teers. Similar effects have also recently been shown inHF patients [3]. The pertinent question therefore – andthe one which the authors have specifically addressed –is why this therapy may be ineffective at improving au-tonomic balance whilst the administration of other NO-based drugs works well.

Although GTN has continued to be successfully usedin the treatment of angina pectoris for over a century,the precise mechanism through which it works in thecontext of what is known about NO-signaling, is unclear.In particular, there appears to be some doubt overwhether this drug leads to NO formation or whether itoperates via a direct action on the downstream media-tors responsible for NO-dependent vasorelaxation [11].

Aside from the mechanistic actions of GTN being po-tentially discreet from other NO donors, the pharmaco-kinetic properties of GTN patches may be inadequate fortargeting NO signaling in the heart or nervous system.Although significant physiological roles of NO have beendemonstrated in a multitude of different cell-types,thereare many tissues in which NO bioavailability is made ex-tremely low,(notably in blood and muscle) because of thehigh concentration of iron-containing heme compoundswhich act as NO-scavengers. For this reason, NO donorsare often unable to replicate the temporal and spatialcharacteristics of endogenous NO-synthesis. In themouse heart, the actions of endogenously synthesizedNO are significantly amplified by myoglobin geneknockout [8] showing that the myoglobin-rich environ-ment of the heart is a significant barrier to NO diffusion.C

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Edward J. F. DansonBurdon-Sanderson Cardiac CentreUniversity of OxfordParks RoadOxford OX1 3PT, UKTel.: +44-1865/282503Fax: +44-1865/272453E-Mail: edward.danson@physiol.ox.ac.uk

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Bearing this in mind, the anatomical localization andtissue type of the intended therapeutic target in Buchet al.’s study is not entirely clear. This is potentially themost confounding aspect of this study’s design. NO maywork as an important regulator of cardiac autonomiccontrol at the level of the brainstem or peripherally inthe heart itself [15]. Although the authors site indirectevidence that transdermal GTN enters the circulationand CNS, there is no evidence as to whether GTN is ca-pable of entering intrinsic cardiac ganglia.

The other complicating factor in the interpretation ofthese data is that, unlike in intracardiac ganglia, NO mayhave opposite effects on different sites within the brain-stem. In particular, vagal activity may be facilitated byNO in the nucleus ambiguus [16], whilst it is inhibited inthe nucleus tractus solitarii [14]. The way in whichpromiscuously-available NO (of unknown concentra-tion) from GTN may act within these environments overtime is not known. However, it is particularly interestingthat other studies demonstrating positive effects of in-fused NO donors on vagal control of heart rate have usedacute administration of the drug, as opposed to thechronic release over 7-days. Although tolerance phe-nomena are rightly addressed as a potential explanationfor this by the authors, there may be the additional prob-lem that the actions of NO in the brainstem are depen-dent on the level of tissue oxidative stress. Indeed, it isbelieved that superoxide dismutase microinjection intothe rostroventrolateral medulla (RVLM) to reduce ox-idative stress in pigs chronically administered with or-ganic nitrates decreases sympathetic nerve activity byup to 70 % [20], suggesting this may have limited the fa-cilitation of HRV by NO.

The way in which heart failure interacts with oxida-

tive stress and NO-bioavailability in various tissues isalso a significant issue in this study. Whilst NO synthe-sis may often be augmented in tissues during heart fail-ure due to enhanced inducible NOS [7] and endothelialNOS activity [9], uncoupling of NO-signaling throughcGMP formation is a common problem due to the abun-dance of superoxide anion, which reacts with NO toform peroxynitrite.Although the effects of peroxynitriteon autonomic balance in humans are not understood,they often negate the effects of NO-cGMP signaling instudies on vascular tissue [19].

In animal models, some of these problems can beovercome by substituting more accurately for the phys-iological production of NO. Gene delivery of nNOS tothe intrinsic cardiac ganglia [13] or the RVLM [18] in-creases vagally-mediated bradycardia. Functionally, thisphenotype mimics that seen following exercise-training[6] and can modulate altered autonomic balance associ-ated with heart failure [18].

The study by Buch et al. demonstrates that conven-tional nitroglycerin treatment is largely ineffective attargeting parasympathetic regulation of heart rate in theclinic. To date, effective chronic modulation of cardiacautonomic balance in patients with reduced HRV there-fore remains an unfinished goal. This study will hope-fully motivate basic researchers and clinicians to worktowards achieving this, in order to fully establish thecausal roles of autonomic dysfunction in cardiac mor-tality and the potential therapeutic targets.

■ Acknowledgement This work was supported by the British HeartFoundation and the James Knott Research Scholarship, St. Cross Col-lege, Oxford University.

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