Contribution of platelets and platelet-activating factor (PAF) to the arrhythmogenic, haemodynamic and necrotic effects of acute myocardial ischaemia

Abstract

The effects of alterations in platelet activity on arrhythmias, haemodynamics and extent of necrosis during coronary ligation for 30 min were assessed in rabbits. Reduction of platelet counts to less than 1% of control by intravenous injection of platelet antiserum (1 ml kg-1 i.v.) reduced the volume of necrosed tissue from 23 +/- 2% to 15 +/- 1%, P less than 0.01 (expressed as % of total LV) and attenuated the hypotensive effect of ischaemia. Pretreatment with the platelet activating factor (PAF) antagonist BN 52021 also attenuated the hypotension and necrosis caused by coronary ligation 23 +/- 2% vs 14 +/- 1%, P less than 0.01. Pretreatment with the thromboxane antagonist CGS 13080 attenuated the hypotensive response to ischaemia but had only a very small effect on the area of necrosis. Administration of PAF at 10 min following coronary ligation markedly increased the volume of necrosed tissue 36 +/- 2%, P less than 0.01 and caused VF and haemodynamic collapse in 10 out of 12 animals. Pretreatment with platelet antiserum or the PAF antagonist BN 52021 reversed this effect of PAF. Pretreatment with CGS 13080 attenuated the marked hypotensive effect of PAF but failed to reverse its necrotic or arrhythmogenic effects. These findings indicate that platelet activation contributes to the necrosis and hypotension following coronary ligation and that platelet-activating factor may contribute to this. The ameliorating effects of platelet antiserum or BN 52021 support the concept that inhibition of platelet activity may have a useful role in the treatment of acute myocardial infarction.

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

“…We have previously used this anaesthetized, open chest rabbit model to investigate the effects, on arrhythmogenesis and necrosis, of modulating PAF activity during myocardial ischaemia (Chakrabarty et al, 1991a). Following coronary artery ligation in the rabbit, there is a significant fall in blood pressure, high incidence of ventricular arrhythmias and a substantial volume of myocardial necrosis.…”

“…It is known that exogenous PAF can induce hypotension in many species, including the rabbit and rat (Yue et al, 1990;Chakrabarty et al, 1991a) and BN50739 has been shown to block this in rats (Yue et al, 1990). Although the mechanism for the hypotensive action of PAF is unclear, a recent study by Yamanaka et al (1992) revealed a biphasic hypotensive response mediated by two different mechanisms, one independent of prostaglandins and involving dilatation of resistance vessels, and the other involving venodilatation and mediated by prostaglandins.…”

“…They were then washed in water and placed in formaldehyde solution for fixation overnight. The sections were photographed with a reference grid on 35 mm colour slides and their projected images were used to measure the areas of infarction (absence of blue staining) and non-infarction (blue staining) by computerized planimetry, as previously described (Chakrabarty et al, 1991a). The volumes of each section were calculated as the product of the planimetered areas and the section thickness.…”

“…Clinical and experimental studies suggest that platelet activation contributes to myocardial necrosis during ischaemia and reperfusion (Mehta & Mehta, 1979;Mikhailidis et al, 1987;R6sen et al, 1987;Wainwright et al, 1989;Chakrabarty et al, 1991a). Release of platelet activating factor (PAF) from the ischaemic myocardium has been demonstrated experimentally and in man (Lotner et al, 1980;Annable et al, 1985;Zimmerman et al, 1985;Montrucchio et al, 1986;Sisson et al, 1987).…”

“…Release of platelet activating factor (PAF) from the ischaemic myocardium has been demonstrated experimentally and in man (Lotner et al, 1980;Annable et al, 1985;Zimmerman et al, 1985;Montrucchio et al, 1986;Sisson et al, 1987). 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).…”