Interaction of vasoactive substances released by platelet‐activating factor in the rat perfused heart

Abstract

1 The coronary vascular effects of platelet-activating factor (PAF) have been intensively studied and it has been proposed that they are mediated by the release of vasoactive substances. In this study, a cascade perfusion model using two rat perfused hearts was developed to investigate the properties of PAF-released vasoactive substances and the interplay of these substances. The properties of the vasoactive substances after an injection of PAF (100pmol) in the rat perfused heart were examined by collecting the effluent from the first heart for the perfusion of a second (recipient) heart. The presence of vasoconstrictor substances in the effluent was characterized by an increase in the perfusion pressure of the recipient heart. 2 Previous exposure of the recipient heart of PAF (100pmol) abolished the response of the heart to subsequent administration of PAF, but did not affect the response of the recipient heart to the effluent. This suggested that the coronary vasoconstrictor response of the recipient heart was not due to the presence of PAF in the effluent but to other vasoactive substances. 3 Pretreatment of the recipient heart with the leukotriene receptor antagonist, L-649,923 (5pM), partially reduced the vasoconstrictor effect of the effluent. Pretreatment of the first heart with indomethacin (2.8 pM) also partially reduced the vasoconstrictor effect of the effluent. The combination of indomethacin pretreatment of the first heart and L-649,923 pretreatment of the recipient heart completely abolished the vasoconstrictor effect of the effluent suggesting that both prostaglandins and leukotrienes are involved in the vasoconstrictor effect of the effluent. 4 Pretreatment of both hearts with L-649,923 or the first heart with the leukotriene synthesis inhibitor (MK-886, 10pUM) completely abolished the vasoconstrictor effect of the effluent. This suggested that the indomethacin sensitive vasoconstrictor component of the effluent might be regulated by leukotrienes in the first heart. However, infusion of leukotrienes (LTB4, LTC4 and LTD4) to the first heart did not reproduce this vasoconstrictor component of the effluent in the recipient heart. 5 In conclusion, our study demonstrated through the use of a leukotriene receptor antagonist, a leukotriene synthesis inhibitor and a cyclo-oxygenase inhibitor that the vasoconstrictor effect of the effluent of the rat perfused heart after an injection of PAF is mediated by leukotrienes and prostaglandins. The ability of leukotriene receptor blockade and inhibition of leukotriene synthesis to mimic the effect of indomethacin indicates that the production and/or release of cyclo-oxygenase products in the effluent by PAF can be modulated by leukotrienes. The inability of exogenously applied leukotrienes to modulate the production and/or the release of cyclo-oxygenase products in the effluent suggests that the PAF-induced production of prostaglandins may be mediated by intracellular leukotrienes or at sites not accessible to exogenously applied leukotrienes.

Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

“…The effects induced by PAF in the isolated rat heart are similar to that observed in guinea pig heart (e.g., reduction in coronary flow and developed pressure, increase in diastolic pressure and conduction arrhythmias) (188,189,334,339,340). In this animal, however, it has been shown that the PAF-induced coronary vasoconstriction is mediated by the peptide leukotrienes (leukotriene C 4 and leukotriene D 4 ) (188,189,334). This finding indicates that in the rat heart PAF may have a small direct negative effect, whereas the reduction of coronary flow consequent to production and release of endogenous leukotrienes appears to induce a major depression of cardiac contractile force.…”

Involvement of nitric oxide and eicosanoids in platelet‐activating factor‐induced haemodynamic and haematological effects in dogs

“…In fact, the vascular effects of PAF have been shown to be largely mediated by the release of other vasoactive substances such as prostaglandins PAF 0.25 jg kg-1 i.v. ( Heffner et al, 1983;Piper & Stewart, 1986;Hu & Man, 1991), leukotrienes (Voelkel et al, 1982;Sybertz et al, 1985;Piper & Stewart, 1986) and PAF itself (Tessner et al, 1989). In addition, several lines of evidence indicate that production of endothelium-derived relaxing factor (EDRF), which is thought to be nitric oxide (NO; Palmer et al, 1987), may contribute to the vasodilator actions of PAF in in vitro preparations (Kamitani et al, 1984;Kamata et al, 1989;Chiba et al, 1990;Moritoki et al, 1992;Juncos et al, 1993).…”

Rabbit polymorphonuclear leukocytes release a factor that causes constriction of the coronary vasculature

“…Another possible mediator of the constrictor effect is PAF, which is produced by PMN and can cause coronary vasoconstriction (11). PAF is reported to cause responses via the synthesis of leukotrienes and prostaglandins (12,35), and, although we were not successful in blocking responses to leukotrienes, indomethacin had no effect on the response, suggesting that PAFinduced prostaglandin production in situ is not a contributing factor in our study. PAF has been reported to cause dilator and constrictor effects that are species dependent (11).…”