Effect of BN 50739, a new platelet activating factor antagonist, on ischaemia induced ventricular arrhythmias in isolated working rat hearts

Abstract

Under in vitro conditions PAF is likely to be involved in the genesis of ischaemia induced ventricular arrhythmias since BN 50739, a specific PAF receptor antagonist, exerts a protective effect against these rhythm disturbances. This suggests that PAF antagonists may have benefit in the clinical management of acute myocardial ischaemia.

Effects of the PAF antagonists BN50726 and BN50739 on arrhythmogenesis and extent of necrosis during myocardial ischaemia/reperfusion in rabbits

“…The antiarrhythmic properties of BN50726 that were observed in this study and the similar trend seen with BN50739 give further evidence for a role of PAF in mediating arrhythmogenesis during myocardial ischaemia, and correlate well with other reports using PAF antagonists (Wainwright et al, 1989;Yue et al, 1990;Koltai et al, 1991a;Chakrabarty et al, 1991a). The exact mechanism through which PAF mediates these effects is not clear.…”

“…Koltai et al (1991a) recently commented on the complexity of the actions of PAF in the whole animal. Interactions between PAF and cytokines may promote cellular necrosis, and PAF may also alter calcium influx and enhance sodium/hydrogen exchange (Koltai et al, 1991a) producing cellular electrophysiological effects which alter the susceptibility to arrhythmogenesis. The relative ability of PAF antagonists to prevent these effects may be important in determining their efficacy in preventing arrhythmogenesis and reducing or delaying the extent of necrosis.…”

“…BN50739 (6-(2-chlorophenyl)-9-[2-(3,4-dimethoxyphenyl) thio]-l-thioxoethyl) -7,8,9,10-tetrahydro-l-methyl]- 4H-pyrido [4'3':4,5] thieno [3,2-fl [1'2'4] triazolo [4,3-a] [1,4] diazepine) and BN50726 (6-(2-chlorophenyl)-9-(hexadecylsulphonyl) -7,8,9,10-tetrahydro-l-methyl-4H-pyrido [4'3':4,5] [4,3-a] [1,4] diazepine) are two novel synthetic PAF antagonists which have been developed recently and shown to be more potent than other compounds in antagonizing the effects of PAF (Yue et al, 1990). Koltai et al (1991a) recently reported that BN50739 reduced the incidence -of ventricular arrhythmias during myocardial ischaemia in rat isolated hearts in the absence of platelets, but relatively little is known about the effects of BN50739 and BN50726 in vivo. To gain further information, we performed experiments designed to examine the haemodynamic, antiarrhythmic and anti-necrotic effects of these PAF antagonists during regional myocardial ischaemia and reperfusion in anaesthetized open chest rabbits.…”

“…Experimental studies have shown that PAF increases myocardial necrosis and arrhythmogenesis (Mickelson et al, 1988;Chakrabarty et al, 1991a) during myocardial ischaemia and that it has direct myocardial cellular electrophysiological and arrhythmogenic effects (Flores & Sheridan, 1990). Recent studies have shown that PAF antagonists have opposite actions, reducing the incidence of arrhythmias and preventing necrosis during ischaemia and reperfusion (Wainwright et al, 1989;Chakrabarty et al, 1991a;Koltai et al, 1991a). Such findings suggest that PAF could play a significant role in the progression and complications of myocardial ischaemia.…”

Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation

“…Clinical trials suggest the mortality benefit of antiplatelet agents, such as aspirin and α IIb β 3 integrin antagonists, may result from effects more complex than simple thrombus inhibition. [9][10][11] In animal studies, several platelet-activating factor antagonists [12][13][14] reduced ischemia-induced VF incidence. Moreover, aspirin pretreatment reduced ischemia-induced VF in various animal models.…”