Lack of selectivity for ventricular and ischaemic tissue limits the antiarrhythmic actions of lidocaine, quinidine and flecainide against ischaemia-induced arrhythmias

Barrett, Terrance D.; Hayes, Eric; Walker, Michael J.

doi:10.1016/0014-2999(95)00406-b

Cited by 35 publications

(27 citation statements)

References 30 publications

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“…In the rat model, the profound AP prolongation that occurs due to early outward K + channel blockade may be highly protective in the rat model, but would not be so in the human, and may conceal the proarrhythmic potential of the drug in ischemic human heart. Still, comparing the performance of flecainide in this rat model, in contrast to RSD1235, it showed very limited efficacy in suppressing ischemia‐induced arrhythmias 18 …”

Section: Discussionmentioning

confidence: 85%

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The Mechanism of Atrial Antiarrhythmic Action of RSD1235

Fedida

Orth

Chen

et al. 2005

Cardiovasc electrophysiol

191

166

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Section: Discussionmentioning

confidence: 85%

“…Experiments were performed using the protocol outlined previously, 18 and all methods used were in accordance with the ethical treatment policies as laid down by the Animal Care Facility at the University of British Columbia. Briefly, male Sprague Dawley rats were anaesthetized with sodium pentobarbital and ventilated.…”

Section: Methodsmentioning

confidence: 99%

The Mechanism of Atrial Antiarrhythmic Action of RSD1235

Fedida

Orth

Chen

et al. 2005

Cardiovasc electrophysiol

191

166

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“…As a general consensus, many antiarrhythmic drug therapies, including sodium channel-blocking agents, may exacerbate cardiac vulnerability through their proarrhythmic effects (2,3,24). Despite these limitations, Lido at therapeutic concentrations remains clinically effective at protecting against ischemia-induced ventricular arrhythmias by converting unidirectional block to bidirectional block (1,2,14,20,36,54,57) and has further advantages of attenuating the accumulation of intracellular Na ϩ and Ca 2ϩ during ischemia (58), delaying intracellular acidosis by slowing ATP utilization (58), limiting neutrophil activation and platelet adhesion (62), and reducing infarct size (42).…”

mentioning

confidence: 99%

Protection against ventricular arrhythmias and cardiac death using adenosine and lidocaine during regional ischemia in the in vivo rat

Canyon

Dobson

2004

American Journal of Physiology-Heart and Circulatory Physiology

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Despite decades of research, there are few effective ways to treat ventricular fibrillation (VF), ventricular tachycardia (VT), or cardiac ischemia that show a significant survival benefit. Our aim was to investigate the combined therapeutic effect of two common antiarrhythmic compounds, adenosine and lidocaine (AL), on mortality, arrhythmia frequency and duration, and infarct size in the rat model of regional ischemia. Sprague-Dawley rats (n = 49) were anesthetized with pentobarbital sodium (60 mg.ml(-1).kg(-1) i.p.) and instrumented for regional coronary occlusion (30 min) and reperfusion (120 min). Heart rate, blood pressure, and a lead II electrocardiogram were recorded. Intravenous pretreatment began 5 min before ischemia and extended throughout ischemia, terminating at the start of reperfusion. After 120 min, hearts were removed for infarct size measurement. Mortality occurred in 58% of saline controls (n = 12), 50% of adenosine only (305 microg.kg(-1).min(-1), n = 8), 0% in lidocaine only (608 microg.kg(-1).min(-1), n = 8), and 0% in AL at any dose (152, 305, or 407 microg.kg(-1).min(-1) adenosine plus 608 microg.kg(-1).min(-1) lidocaine, n = 7, 8, and 6). VT occurred in 100% of saline controls (18 +/- 9 episodes), 50% of adenosine-only (11 +/- 7 episodes), 83% of lidocaine-only (23 +/- 11 episodes), 60% of low-dose AL (2 +/- 1 episodes, P < 0.05), 57% of mid-dose AL (2 +/- 1 episodes, P < 0.05), and 67% of high-dose AL rats (6 +/- 3 episodes). VF occurred in 75% of saline controls (4 +/- 3 episodes), 100% of adenosine-only-treated rats (3 +/- 2 episodes), and 33% lidocaine-only-treated rats (2 +/- 1 episodes) of the rats tested. There was no deaths and no VF in the low- and mid-dose AL-treated rats during ischemia, and only one high-dose AL-treated rat experienced VF (25.5 sec). Infarct size was lower in all AL-treated rats but only reached significance with the mid-dose treatment (saline controls 61 +/- 5% vs. 38 +/- 6%, P < 0.05). We conclude that a constant infusion of a solution containing AL virtually abolished severe arrhythmias and prevented cardiac death in an in vivo rat model of acute myocardial ischemia and reperfusion. AL combinational therapy may provide a primary prevention therapeutic window in ischemic and nonischemic regions of the heart.

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“…Na + channel block results in prominent decreases in abnormal automaticity [71][72] and strongly decreases ectopic complex frequency [73]. Extra-cardiac toxicity is the main dose-limiting complication and can appear concurrently with anti-arrhythmic activity, [74][75][76] but the main factor limiting clinical use is the potential for proarrhythmia.…”

Section: Sodium Current (I Na )mentioning

confidence: 99%

Novel Targets for Cardiac Antiarrhythmic Drug Development

Hesketh¹,

Herrera²,

Zicha³

et al. 2005

CPD

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Cardiac arrhythmias remain a major source of morbidity and mortality in developed countries. Antiarrhythmic drug therapy was traditionally the mainstay of cardiac arrhythmia treatment; however, drug therapy of cardiac arrhythmias has been plagued by incomplete efficacy and by potentially serious adverse reactions, of which the most worrisome has been a potential for malignant proarrhythmia and related effects to increase cardiac mortality. This article reviews the principal arrhythmia mechanisms and their ionic determinants, and discusses potential innovative approaches to new antiarrhythmic drug development, including the consideration of novel ionic targets, potential biophysical approaches and non-channel components involved in composing the arrhythmic substrate.

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Lack of selectivity for ventricular and ischaemic tissue limits the antiarrhythmic actions of lidocaine, quinidine and flecainide against ischaemia-induced arrhythmias

Cited by 35 publications

References 30 publications

The Mechanism of Atrial Antiarrhythmic Action of RSD1235

The Mechanism of Atrial Antiarrhythmic Action of RSD1235

Protection against ventricular arrhythmias and cardiac death using adenosine and lidocaine during regional ischemia in the in vivo rat

Novel Targets for Cardiac Antiarrhythmic Drug Development

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