Protection Against Ventricular Fibrillation by the PAF Antagonist, BN-50739, Involves an Ischaemia-Selective Mechanism

Abstract

The platelet-activating factor (PAF) antagonist BN-50739 can suppress certain cardiac arrhythmias. PAF is released from ischaemic myocardium and may contribute to initiation of ischaemia-induced ventricular fibrillation (VF). In this study we characterised the action of BN-50739 on left regional ischaemia-induced VF and examined whether effects are mediated within the ischaemic territory, or are nonspecific. In rat isolated Langendorff perfused hearts (n = 12/group), 10 microM BN-50739 reduced the incidence of ischaemia-induced VF from 75 to 17% (p<0.05). This was accompanied by QT widening and an increase in coronary flow. Heart rate and PR interval were not affected by the drug. In separate studies, isolated rat hearts were perfused by using a dual-lumen tube that allows independent delivery of solution to the left and right coronary beds. Successful regional localisation of drug delivery was confirmed by observing, before ischaemia, a regionally selective increase in coronary flow (p<0.05), measured by using two in-line flow meters. Protection against ischaemia-induced VF (p<0.05) was achieved by pretreatment with BN-50739, delivered selectively and entrapped within the involved region, but not when the drug was delivered to the uninvolved region. In conclusion, BN-50739 protects against ischaemia-induced VF by eliciting a pharmacologic action in the involved (ischaemic) myocardium. This supports the hypothesis that BN-50739 suppresses an arrhythmogenic effect of endogenous PAF released within the ischaemic tissue.

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)

“…Because PAF is present in the inflammatory milieu following coronary ischemia (32), there has been interest in investigating PAFR antagonists as antiarrhythmic agents in ischemia-reperfusion injury. Indeed, PAFR antagonism has been shown to be effective in preventing post-ischemia arrhythmias ex vivo (33) and in vivo (34,35). Unfortunately, one PAFR antagonist has been shown to promote QT interval prolongation and coronary vasodilation, resulting in hypotension and arrhythmogenic potential (33).…”

“…Indeed, PAFR antagonism has been shown to be effective in preventing post-ischemia arrhythmias ex vivo (33) and in vivo (34,35). Unfortunately, one PAFR antagonist has been shown to promote QT interval prolongation and coronary vasodilation, resulting in hypotension and arrhythmogenic potential (33). Although these do not The mean (Ϯ S.E.)…”

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

“…This minimises the scope for cross‐flow between the independently perfused left and right coronary beds ( Avkiran & Curtis, 1991 ). In addition, the rat is the species used in our previous studies on ischaemia‐induced VF and effects of PAF antagonists ( Baker & Curtis, 1999 ).…”

“…Several separate pieces of evidence support this. For example, PAF accumulates in the ischaemic myocardium ( Berti et al ., 1990 ), exogenously applied PAF worsens the severity of low‐flow global ischaemia‐induced VF ( Flores & Sheridan, 1990 ), and the PAF antagonist BN‐50739 protects against ischaemia‐induced VF when delivered to the left (and subsequently ischaemic) coronary bed ( Baker & Curtis, 1999 ). However, these data all have their limitations.…”

“…To resolve these problems, in the present study we have made use of a preparation that replaces the normal Langendorff aortic cannula with dual lumen catheter to perfuse independently the left and right coronary beds of an isolated heart ( Avkiran & Curtis, 1991 ). When coronary flow to the left coronary bed is selectively shut off in this preparation, this results in ischaemia and arrhythmias that are almost identical to those evoked by coronary ligation in the standard rat Langendorff arrhythmia bioassay ( Rees & Curtis, 1995a ; Baker & Curtis, 1999 ), making the preparation ideal for the study of putative mediators of ischaemia‐induced VF and thus preferable to global perfusion/ischaemia models. The preparation additionally allows the monitoring of effects on rhythm and antecedent variables such as heart rate and coronary flow, without the confounding influence of nerves, blood and hormones ( Avkiran & Curtis, 1991 ).…”