title: 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.
authors.affiliation: The King's Centre for Cardiovascular Research (Myocardial Ischaemia, Infarction and Reperfusion I.R.G.), Guy's, King's, and St. Thomas' School of Biomedical Sciences, University of London, England, UK.
authors.forename: K E
authors.initials: KE
authors.lastname: Baker
authors.forename: M J
authors.initials: MJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001381:Azepines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy*; D010477:Perfusion; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D020011:Protective Agents / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D001381:Azepines; D010972:Platelet Activating Factor; D020011:Protective Agents; D014230:Triazoles; C064509:BN 50739