Vagal modulation of dispersion of repolarisation in the rabbit heart

Winter, James; Lee, Angela W.C.; Niederer, Steven A.; Shattock, Michael J.

doi:10.1016/j.yjmcc.2015.05.011

Cited by 10 publications

(16 citation statements)

References 54 publications

(33 reference statements)

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“…The innervated rabbit heart preparation was isolated as previously described 28 . All animals were euthanized by sodium pentobarbitone overdose (160 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

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Restitution slope is principally determined by steady-state action potential duration

Shattock

Park

Yang

et al. 2017

Cardiovascular Research

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AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and resultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.

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“…The innervated rabbit heart preparation was isolated as previously described 28 . All animals were euthanized by sodium pentobarbitone overdose (160 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Nerves were isolated and stimulated as previously described 28 . Dynamic restitution relationships were measured at baseline and during vagus nerve stimulation at 10 or 50 Hz (5 V, 2-ms pulse duration).…”

Section: Methodsmentioning

confidence: 99%

Restitution slope is principally determined by steady-state action potential duration

Shattock

Park

Yang

et al. 2017

Cardiovascular Research

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“…(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%

“…(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.…”

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confidence: 93%

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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“…159 It is currently unclear if this effect is exclusively mediated by bradycardia-induced I Na,L enhancement or whether a direct impact of muscarinic stimulation on ion channels plays a significant role here. 144,159,160…”

Section: Ventricular Arrhythmogenesis and The Autonomic Nervous Systemmentioning

confidence: 99%

Ventricular arrhythmogenesis in the genetically-susceptible heart

Bekke

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Vagal modulation of dispersion of repolarisation in the rabbit heart

Cited by 10 publications

References 54 publications

Restitution slope is principally determined by steady-state action potential duration

Restitution slope is principally determined by steady-state action potential duration

Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

Ventricular arrhythmogenesis in the genetically-susceptible heart

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