Effects of anipamil, a long acting analog of verapamil, in pigs subjected to myocardial ischemia

Ries, Craig R.; Guppy, Leon J.; Harvie, C.J.; Walker, Michael J.

doi:10.1016/0024-3205(95)02070-y

Cited by 7 publications

(11 citation statements)

References 23 publications

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“…Consistent with published data [13], there appeared to be three distinct phases of high arrhythmia incidence: Phase 1a arrhythmias occurred in the period from 0 to 20 minutes post ligation, Phase 1b arrhythmias occurred in the period from 20 to 50 minutes post ligation, and Phase 2 occurred in the period from 50 to 180 minutes [14], [15], [16].…”

Section: Resultssupporting

confidence: 87%

“…Phase 1a arrhythmias are generally considered to commence between 0 and 5 minutes post coronary artery occlusion [13], [22], [23] and terminate between 3 and 20 minutes post occlusion [24], [25], [26]. Phase 1b arrhythmias are generally defined as commencing between 5 and 20.5 minutes [13], [16], [27] and terminating between 18 and 90 minutes post occlusion [24], [28], [29], [30]. Phase 2 arrhythmias commence after phase 1b [16].…”

Section: Discussionmentioning

confidence: 99%

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The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

Weiss

Saint

2010

PLoS ONE

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BackgroundThe potential of the cardiac persistent sodium current as a target for protection of the myocardium from ischaemia and reperfusion injury is gaining increasing interest. We have investigated the anti-ischaemic and antiarrhythmic effects of riluzole, a selective INaP blocker, in an open chest pig model of infarction.Methods and Principal FindingsThe left anterior descending coronary artery (LAD) was ligated in 27 anesthetised pigs (landrace or large white, either sex, 20–35 kg) which had received riluzole (8 mg/kg IP; n = 6), lidocaine (2.5–12 mg/kg bolus plus 0.05–0.24 mg/kg/min; n = 11) or vehicle (n = 10) 50 min prior. Arrhythmias could be delineated into phase 1a (0 to 20 min), phase 1b (20 to 50 min) and phase 2 (from 50 min to termination at 180 min) and were classified as premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (spontaneously reverting within 15 s) or sustained VT or VF (ie. requiring cardioversion at 15 s). Riluzole reduced the average number of all arrhythmias in Phase 2 (PVCs from 484+/−119 to 32+/−13; non sustained arrhythmias from 8.9+/−4.4 to 0.7+/−0.5; sustained arrhythmias from 3.9+/−2.2 to 0.5+/−0.4); lidocaine reduced the average number of non-sustained and sustained arrhythmias (to 0.4+/−0.3 and 0.4+/−0.3 respectively) but not PVCs (to 390+/−234). Riluzole and lidocaine reduced the average number of sustained arrhythmias in phase 1b (from 1.8+/−0.4 to 0.17+/−0.13 (p<0.02) and to 0.55+/−0.26 (p = ns) respectively). Neither lidocaine or riluzole changed the ECG intervals: there was no statistical significance between groups at time zero (just before ligation) for any ECG measure. During the course of the 3 hour period of the ischaemia R-R, and P-R intervals shortened slightly in control and riluzole groups (not significantly different from each other) but not in the lidocaine group (significantly different from control). QRS and QTc did not change appreciably in any group Riluzole reduced the degree of histopathological tissue damage across the infarct zone considerably more than did lidocaine.ConclusionsAt the doses used, riluzole was at least as effective as lidocaine at reducing the number of episodes of ischaemic VT or VF in pigs, and much more effective at reducing the number of PVCs. We propose that this is related to the ability of riluzole to block cardiac persistent sodium current.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

Weiss

Saint

2010

PLoS ONE

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“…VT, prolongation of QTc interval and TdP were detected with bepridil treatment in permanent AF patients, while no ventricular arrhythmias were seen with amiodarone [134]. Anipamil was also found arrhythmogenic at least in pentobarbitone-anesthetized pigs where it increased the occurrence of VT and VF [135], [136]. In rats with healed infarcts and ventricular dysfunction, 8-week-long anipamil treatment aggravated left ventricular dilatation and remodeling, thereby reduced survival [136].…”

Section: Proarrhythmic Actions Of Ccasmentioning

confidence: 99%

“…In pentobarbitone-anesthetized pigs, intravenous anipamil exerted arrhythmogenic action as it increased the occurrence of VT and VF. On the contrary, verapamil, in a dose which produced similar hemodynamic effects than those of anipamil, reduced the occurrence of VT and VF [135], [136]. 8-week-long anipamil treatment aggravated left ventricular dilatation and remodeling, thereby reduced survival in rats with healed infarcts and ventricular dysfunction [136].…”

Section: Anipamil Animal Studies With Anipamilmentioning

confidence: 99%

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Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Szentandrássy

Nagy²,

Hegyi³

et al. 2014

CPD

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Cardiac arrhythmias are a major cause of morbidity and mortality in the industrialized world. Among their treatment regimens one can find the calcium channel antagonists (CCAs), the class IV agents. In the cardiovascular system Land T-type calcium channels are found on vascular smooth muscle cells and cardiac myocytes with well defined physiological roles. Inhibition of calcium channels by CCAs has widely been used in clinical practice for several decades. Cardiovascular disorders are one of the many fields of medicine in which CCAs are used for various reasons and conditions. The three main indications of them are hypertension, angina and various cardiac arrhythmias. The most important classes of CCAs are dihydropyridines, phenylalkylamines and benzothiazepines but some newer compounds do not fall into any of these major classes. Dihydropyridines are not used in the antiarrhythmic therapy but are good vasodilators and antianginal agents. In contrast, phenylalkylamines and benzothiazepines exert cardiac actions in vivo and therefore these are one choice of antiarrhythmic drugs. This review focuses on phenylalkylamines, benzothiazepines and on new drugs with potential antiarrhythmic action in the heart as well as the mechanisms how calcium channels antagonism can lead to an antiarrhythmic action.

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Phase 2 ventricular arrhythmias in acute myocardial infarction: a neglected target for therapeutic antiarrhythmic drug development and for safety pharmacology evaluation

Clements‐Jewery

Hearse

Curtis

2005

British J Pharmacology

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Ventricular fibrillation (VF), a cause of sudden cardiac death (SCD) in the setting of acute myocardial infarction (MI), remains a major therapeutic challenge. In humans, VF may occur within minutes or hours after the onset of chest pain, so its precise timing in relation to the onset of ischaemia is variable. Moreover, because VF usually occurs unobserved, out of hospital, and is usually lethal in the absence of intervention, its precise timing of onset is actually unknown in most patients. In animal models, the timing of susceptibility to VF is much better characterised. It occurs in two distinct phases. Early VF (defined as phase 1 VF, with possible subphases 1a and 1b in some animal species) occurs during the first 30 min of ischaemia when most myocardial injury is still reversible. Late VF, defined as phase 2 VF, occurs when myocardial necrosis is becoming established (after more than 90 min of ischaemia). Although much is known about the mechanisms and pharmacology of phase 1 VF, little is known about phase 2 VF. By reviewing a range of different types of data we have outlined the likely mechanisms and clinical relevance of phase 2 VF, and have evaluated possible future directions to help evolve a strategy for its suppression by drugs. The possibility that a proarrhythmic effect on phase 2 VF contributes to the adverse cardiac effects of certain cardiac and noncardiac drugs is also discussed in relation to the emerging field of safety pharmacology. It is concluded that suppression of phase 2 as well as phase 1 VF will almost certainly be necessary if drugs of the future are to achieve what drugs of the past and present have failed to achieve: full protection against SCD. Likewise, safety will require avoidance of exacerbation of phase 2 as well as phase 1 VF.

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Effects of anipamil, a long acting analog of verapamil, in pigs subjected to myocardial ischemia

Cited by 7 publications

References 23 publications

The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Phase 2 ventricular arrhythmias in acute myocardial infarction: a neglected target for therapeutic antiarrhythmic drug development and for safety pharmacology evaluation

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