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

Abstract

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:

Ability to Induce Atrial Fibrillation in the Peri-operative Period Is Associated with Phosphorylation-dependent Inhibition of TWIK Protein-related Acid-sensitive Potassium Channel 1 (TASK-1)

“…Exogenous PAF caused ventricular tachycardias in Langendorff-perfused rat hearts (29) and potentiated ischemia-induced arrhythmias in Langendorff-perfused guinea pig hearts (30). In mice, overexpression of the PAF receptor (PAFR) as a transgene resulted in increased sensitivity to PAF-induced arrhythmias (31).…”

Acute myocardial ischemia: Cellular mechanisms underlying ST segment elevation

“…(9) Intracellular acidification activates the Na+/H+ exchanger resulting in H+ extrusion in exchange for Na+ entry, which in turn results in calcium overload by means of activation of the Na+/Ca++ exchanger. The consequent electrophysiological changes include depolarization, Na+ channel inactivation (causing a reduction in peak I Na ) and slow conduction.…”

Cumulative Experience of Azimilide-Associated Torsades de Pointes Ventricular Tachycardia in the 19 Clinical Studies Comprising the Azimilide Database

“…Only 7 of 56 (13%) of patients with azimilide-associated TdP were taking both aspirin and statins, compared with 1,322 of 5,319 (25%) non-TdP patients. Although this may well be a chance finding, it may be related to the cardiovascular benefits of these drugs, such as the anti-inflammatory effects (26 -29) or the antiplatelet effects of aspirin (30). An alternative (practical) explanation is that the use of aspirin was lower in patients with AF because of the use of warfarin.…”