Biochemical Mediators of Ventricular Arrhythmias in Ischemic Heart Disease

Various putative drug targets for suppression of ischaemia‐induced ventricular fibrillation (VF) have been proposed, but therapeutic success in the suppression of sudden cardiac death (SCD) has been disappointing. Platelet‐activating factor (PAF) is a known component of the ischaemic milieu. We examined its arrhythmogenic activity, and its interaction with two other putative mediators, norepinephrine and K+, using an ischaemia‐free in vitro heart bioassay, and a specific PAF antagonist (BN‐50739). PAF (0.1–100 nmol) was administered selectively to the left coronary bed of rat isolated hearts using a specially designed catheter. In some hearts, PAF was administered to the left coronary bed during concomitant regional perfusion with norepinephrine and/or K+. In separate studies, PAF accumulation in the perfused cardiac tissue was evaluated using 3H‐PAF. PAF evoked ventricular arrhythmias concentration‐dependently (P<0.05). It also widened QT interval and reduced coronary flow selectively in the PAF‐exposed left coronary bed (both P<0.05). Two exposures of hearts to PAF were necessary to evoke the QT and rhythm effects. The PAF‐induced arrhythmias and coronary vasoconstriction were partially suppressed by the PAF antagonist BN‐50739 (10 μM), although BN‐50739 itself widened QT interval. K+ (8 and 15 mM) unexpectedly antagonised the arrhythmogenic effects of PAF without itself eliciting arrhythmias (P<0.05). Norepinephrine (0.1 μM) had little or no effect on the actions of PAF, while failing to evoke arrhythmias itself. Nevertheless, the combination of 15 mM K+ and 0.1 μM norepinephrine evoked arrhythmias of a severity similar to arrhythmias evoked by PAF alone, without adding to or diminishing the arrhythmogenic effects of PAF. 3H‐PAF accumulated in the cardiac tissue, with 43±5% still present 5 min after bolus administration, accounting for the need for two exposures of the heart to PAF for evocation of arrhythmias. Thus, PAF, by activating specific receptors in the ventricle, can be expected to contribute to arrhythmogenesis during ischaemia. However, its interaction with other components of the ischaemic milieu is complex, and selective block of its actions (or its accumulation) in the ischaemic milieu is alone unlikely to reduce VF/SCD. British Journal of Pharmacology (2004) 142, 352–366. doi:

Section: Introductionmentioning

confidence: 99%

Left regional cardiac perfusion in vitro with platelet‐activating factor, norepinephrine and K⁺ reveals that ischaemic arrhythmias are caused by independent effects of endogenous ‘mediators’ facilitated by interactions, and moderated by paradoxical antagonism

Baker

Curtis

2004

“…The Kenedi & Losonci (1973) model involves one‐stage coronary artery ligation, and was described first as a method for use in rats. It would perhaps be better known as the Parratt / Szekeres / Walker model, as these were the investigators who independently adapted it, and used it extensively for the study of VF and its suppression (for reviews, see Curtis et al ., 1987; Clements‐Jewery & Curtis, 2003). The model was initially developed to downsize to small animals and simplify the first Harris (1948) model to allow convenient study of the arrhythmias occurring during a brief (30 min) period of ischaemia (e.g., Au et al ., 1979), but was subsequently modified by simply extending the duration of the experiment.…”

Section: Characteristics Of Phase 2 Versus Phase 1 Vf In Regional Iscmentioning

confidence: 99%

“…The rise in membrane potential attenuates the amplitude and upstroke velocity of the action potential as a result of Na + channel inactivation, and action potential duration typically lengthens and then shortens with prolonged ischaemia probably as a result of enhanced outward repolarising K + currents (Cascio et al ., 1995). The phase 1 period is also associated with the intercellular accumulation of many biochemicals, including catecholamines, K + , and amphiphiles such as lysophosphatidylcholine and platelet‐activating factor, and although many have arrhythmogenic properties, no individual substance has yet been identified as being both sufficient and necessary for mediation of phase 1 VF (Curtis, 1993; Curtis et al ., 1993b; Clements‐Jewery & Curtis, 2003; Baker & Curtis, 2004).…”

Section: Biochemical and Electrophysiological Events Underlying Phasementioning

confidence: 99%

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

Self Cite

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.

“…Despite an overall fall in mortality in patients with coronary artery disease over the last decade, mortality from ventricular fibrillation (VF) is not declining (Zheng et al ., 2001). Inhibition of the actions of endogenous chemical mediators of the initiation of ventricular arrhythmia (Curtis et al ., 1993) is an underexploited alternative to targeting cardiac ion channels as an approach to antiarrhythmic drug development (Clements‐Jewery and Curtis, 2003).…”

Section: Introductionmentioning

confidence: 99%

Nupafant, a PAF‐antagonist prototype for suppression of ventricular fibrillation without liability for QT prolongation?

Baker

Wood

Whittaker

et al. 2006

Background and purpose: PAF antagonists inhibit ischaemia-induced ventricular fibrillation (VF) in animals. However, unfavourable ancillary actions (on QT interval and coronary flow) have been reported with the PAF antagonist, BN-50739. If these are class actions, they would preclude development of PAF antagonists as novel anti-VF drugs. Our purpose was to examine this proposition using the hitherto untested PAF antagonist, nupafant. Experimental approach: Two rat heart preparations (Langendorff and 'dual coronary' perfusion) were used to assay nupafant's effects on ischaemia-induced VF, coronary flow and QT interval, and to test for the site-selectivity necessary if any effects on VF are caused by PAF antagonism. Key results: Global (whole-heart) delivery of 10 mM nupafant, reduced the incidence of ischaemia-induced VF and widened QT interval without affecting coronary flow. Importantly, lower concentrations (0.1 and 1 mM) had no effect on VF, yet widened QT almost identically to 10 mM nupafant. When nupafant was delivered selectively to (and entrapped within) the involved region it partially protected against VF (Po0.05). This occurred without change in QT interval. Selective nupafant delivery to the uninvolved region was without effect. Conclusions and implications: Nupafant protects against ischaemia-induced VF primarily by site-selective actions in the ischaemic region but, unlike BN-50739, the effect is unrelated to its QT widening action, and is not compromised by any effect on coronary flow. This establishes proof of concept that VF suppression by PAF antagonism need not invariably be associated with QT prolongation or vasodilatation, justifying further development of this drug class.