Effects of Direct Sympathetic and Vagus Nerve Stimulation on the Physiology of the Whole Heart – A Novel Model of Isolated Langendorff Perfused Rabbit Heart with Intact Dual Autonomic Innervation

Ng, Guseva; Brack, Kieran E.; Coote, John H.

doi:10.1113/eph8602146

Cited by 127 publications

(162 citation statements)

References 19 publications

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“…(Brack et al, 2006) Baseline heart rates were markedly greater in our study than in previous studies (perhaps due to improved perfusion) and so it stands to reason that hearts may be initially operating on the downward slope of the bi-phasic force-frequency curve. (Brack et al, 2006;Ng et al, 2001;Winter et al, 2015) However, we cannot rule out that the positive inotropic response to VNS reflects the low oxygen carrying capacity of the Krebs buffer and resulting improved energetics when heart rate is slowed. The influence of hyoscine and physostigmine on the inotropic response to VNS are likely to be secondary to effects on heart rate (i.e.…”

Section: Discussionmentioning

confidence: 94%

“…(Möller et al, 1999) The finding that VNS caused an increase in LVP appears at odds with previous reports suggesting that vagal stimulation decreases ventricular force in the rabbit heart. (Brack et al, 2006;Ng et al, 2001;Winter et al, 2015) However, Ng et al (2006) reported a bi-phasic force-frequency response, consisting of an initial increase followed by a secondary decrease in ventricular force with increasing heart rate. (Brack et al, 2006) Baseline heart rates were markedly greater in our study than in previous studies (perhaps due to improved perfusion) and so it stands to reason that hearts may be initially operating on the downward slope of the bi-phasic force-frequency curve.…”

Section: Discussionmentioning

confidence: 99%

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Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

et al. 2016

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(242 words)Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors is an effective strategy for reducing lethality following organophosphate nerve agent exposure. AChE inhibition may have unwanted cardiac side effects, which could be negated by adjunctive anti-cholinergic therapy. The aims of the present study were to examine the concentration-dependent effects of physostigmine on cardiac responses to vagus nerve stimulation (VNS), to test whether adjunctive treatment with hyoscine can reverse these effects and to assess the functional interaction and electrophysiological consequences of a combined pre-treatment. Studies were performed in an isolated innervated rabbit heart preparation. The reduction in heart rate with VNS was augmented by physostigmine (1-1000nmol/L), in a concentration-dependent manner -with an EC 50 of 19nmol/L. Hyoscine was shown to be effective at blocking the cardiac responses to VNS with an IC 50 of 11nmol/L. With concomitant perfusion of physostigmine, the concentration-response curve for hyoscine was shifted downward and to the right, increasing the concentration of hyoscine required to normalise (to control values) the effects of physostigmine on heart rate. At the lowest concentration of hyoscine examined (1nmol/L) a modest potentiation of heart rate response to VNS (+15±3%) was observed. We found no evidence of cardiac dysfunction or severe electrophysiological abnormalities with either physostigmine or hyoscine alone, or as a combined drug-therapy. The main finding of this study is that hyoscine, at concentrations greater than 10 -8 M, is effective at reversing the functional effects of physostigmine on the heart. However, low-concentrations of hyoscine may augment cardiac parasympathetic control. Keywords acetylcholinesterase; organophosphate nerve agents; vagus nerve; physostigmine; hyoscine; scopolamine; eserine 3 IntroductionExposure to highly toxic organophosphate nerve agents results in irreversible inhibition of peripheral and central acetylcholinesterase (AChE) resulting in acetylcholine accumulation and over-stimulation of muscarinic and nicotinic receptors. Symptoms of nerve agent poisoning include hyper-secretion, convulsions, respiratory distress, coma and death.Numerous studies in non-primates and non-human primates have shown that pre-treatment with reversible cholinesterase inhibitors, with and without anticholinergics, improves survival and reduces incapacitation after nerve agent exposure. (Bonhage et al., 2009;Lim et al., 1991;Lim et al., 1988;Muggleton et al., 2003;Philippens et al., 1998;Philippens et al., 2000;von Bredow et al., 1991;Wetherell et al., 2002;Wetherell, 1994) Pyridostigmine (a quaternary compound restricted primarily to the peripheral nervous system) and physostigmine (a neutral compound which can more readily pass the blood brain barrier) are long acting, but reversible, AChE inhibitors that are effective pre-treatments for nerve-agent exposure. While both agents are effective in preventing lethality in animal studies, physos...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

et al. 2016

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“…In order to investigate the mechanisms underlying the autonomic modulation of VF, our group developed an in vitro Langendorff perfused innervated rabbit heart preparation (Ng et al 2001b) which allows controlled stimulation of autonomic nerves without the confounding influence of underlying tonic autonomic activity, haemodynamic reflexes, circulating hormones or anaesthetics. Stimulating sympathetic inputs from within the spinal cord, reduced the stimulus current required to induce VF i.e.…”

Section: Sympathetic Nerve Stimulation Apd Restitution and Vfmentioning

confidence: 99%

“…Using the innervated heart preparation (Ng et al 2001b), our group studied the effects of VNS on electrical restitution and VFT (Ng 2014). …”

Section: Direct Anti-vf Protection -Studies In the Isolated Innervatementioning

confidence: 99%

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

2016

Autonomic Neuroscience

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Sudden cardiac death as a result of lethal ventricular arrhythmias is a major cause of death in cardiac diseases such as heart failure and prior myocardial infarct. Activity of the autonomic nervous system is often abnormal where sympathetic activity is upregulated and vagal activity reduced in these conditions. The abnormal autonomic state has been shown to be a strong prognostic marker of increased mortality and propensity to lethal arrhythmias, for which there is no effective prevention. Research effort over the years has established good evidence for a causal link between autonomic disturbance and ventricular arrhythmias. However, the detailed electrophysiological mechanisms by which ventricular fibrillation occurs are still not clear and molecular processes which are modulated by autonomic nerve influences that either predispose the heart to or protect it from these arrhythmias are not fully understood. This review presents data from studies investigating the link between activity of the autonomic nervous system and ventricular arrhythmias, from seminal findings in classical studies to ongoing investigations, in the quest for a better understanding of the arrhythmogenic mechanisms underlying neurocardiac interactions with a view to the development of effective preventative and therapeutic strategies which are very much needed.

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“…In addition, the proportion of conflict trials across a task block was manipulated, using low-conflict (75% no-conflict and 25% conflict trials) and high-conflict (25% no-conflict and 75% conflict trials) task blocks that were presented in alternating order. On the basis of the known temporal dynamics of beta-adrenergic influence on the heart (Mokrane & Nadeau, 1998;Ng, Brack, & Coote, 2001), it is expected that the effects of trial conflict on RZ only emerge after 1 to 3 seconds following stimulus onset. On the other hand, based on earlier studies it is expected that the effect of trial conflict on cardiac deceleration emerges approximately 1 second after stimulus onset (i.e., the first interbeat interval following stimulus onset) and lasts for about 1 second (Fiehler et al, 2004;Jennings et al, 1991;Spapé & Ravaja, 2016).…”

Section: Introductionmentioning

confidence: 99%

How effortful is cognitive control? Insights from a novel method measuring single-trial evoked beta-adrenergic cardiac reactivity

Kuipers

Richter

Scheepers

et al. 2017

International Journal of Psychophysiology

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in press). How effortful is cognitive control? Insights from a novel method measuring singe-trial evoked beta-adrenergic cardiac reactivity. International Journal of Psychophysiology. AbstractThe ability to adjust attentional focus to varying levels of task demands depends on the adaptive recruitment of cognitive control processes. The present study investigated for the first time whether the mobilization of cognitive control during response-conflict trials in a flanker task is associated with effort-related sympathetic activity as measured by changes in the RZinterval at a single-trial level, thus providing an alternative to the pre-ejection period (PEP) which can only be reliably measured in ensemble-averaged data. We predicted that response conflict leads to a physiological orienting response (i.e. heart rate slowing) and increases in effort as reflected by changes in myocardial beta-adrenergic activity (i.e. decreased RZ interval). Our results indeed showed that response conflict led to cardiac deceleration and decreased RZ interval. However, the temporal overlap of the observed heart rate and RZ interval changes suggests that the effect on the latter reflects a change in cardiac pre-load (Frank-Starling mechanism). Our study was thus unable to provide evidence for the expected link between cognitive control and cardiovascular effort. However, it demonstrated that our single-trial analysis enables the assessment of transient changes in cardiac sympathetic activity, thus providing a promising tool for future studies that aim to investigate effort at a single-trial level.

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Effects of Direct Sympathetic and Vagus Nerve Stimulation on the Physiology of the Whole Heart – A Novel Model of Isolated Langendorff Perfused Rabbit Heart with Intact Dual Autonomic Innervation

Cited by 127 publications

References 19 publications

Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

How effortful is cognitive control? Insights from a novel method measuring single-trial evoked beta-adrenergic cardiac reactivity

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