Mechanisms of the coronary vascular effects of platelet‐activating factor in the rat perfused heart

Abstract

1In a previous study it was demonstrated that bolus injections of platelet-activating factor (PAF) in the rat perfused heart resulted in coronary vasodilatation, vasoconstriction or the combination of both, depending on the amount of PAF that was injected. In the present study, the mechanisms of these coronary vascular effects of PAF in the rat perfused heart were investigated. 2 Pretreatment of the rat perfused heart with the PAF antagonists FR-900452 or BN-52021 did not affect the vasodilator effect of PAF but eliminated the vasoconstrictor effect of PAF. FR-900452 had no effect on the vasoconstrictor response to leukotriene C4 (LTC4) or LTD4. 3 The cyclo-oxygenase inhibitor, indomethacin, did not modify the coronary vascular effects of PAF. However L-649,923 (a leukotriene antagonist) and MK-886 (a leukotriene synthesis inhibitor) eliminated both the vasodilator and vasoconstrictor effects of PAF. 4 When leukotrienes were administered by bolus injection in the rat perfused heart, LTB4 produced vasodilatation while LTC4 and LTD4 produced vasoconstriction. L-649,923 blocked both the vasodilator and vasoconstrictor effects of the leukotrienes tested. 5 The results suggest that lipoxygenase products are responsible for both the vasodilator and vasoconstrictor actions of PAF in the coronary vasculature of the rat perfused heart while the cyclo-oxygenase products do not play a significant role. The ineffectiveness of PAF antagonists in blocking the vasodilatation produced by PAF is compatible with the concept that there may be multiple PAF receptors.

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

“…This is consistent with the concept that PAF itself does not directly initiate the coronary vascular effects but mediates its effects through the release of other vasoactive substances (Piper & Stewart, 1986;Hu et al, 1991). Our results showed that one PAF-induced vasoconstrictor component in the effluent was mediated by leukotrienes (blocked by the leukotriene receptor antagonist in the recipient heart or the leukotriene synthesis inhibitor in the first heart) while another component was mediated by cyclo-oxygenase products (blocked by the cyclo-oxygenase inhibitor pretreatment in the.--fis ha t).Us-f the cascade 1 modelenable usl to% study the interplay of the various vasoactive substances in mediating the coronary vascular effects of PAF.…”

“…More recently, we showed that LTC4 and LTD4 may be responsible for the vasoconstrictor effect while LTB4 may be responsible for the vasodilator effect of PAF in the rat perfused heart (Hu et al, 1991). Inasmuch as the precise mechanisms of actions of PAF on circulatory function have not been fully elucidated, the complex interactions between PAF and archidonic acid metabolities in the coronary vascular effects of PAF are also not well defined.…”

“…The perfusion pressure was recorded on a Gould chart recorder and monitored with a digital display. The detailed methodology of the isolated heart perfusion system had been reported previously (Hu et al, 1991).…”

Differential actions of platelet‐activating factor (PAF) receptor antagonists on the vasodilator and vasoconstrictor effects of PAF in the rat perfused heart

“…However, vasodilatation, vasoconstriction and the combination of both responses could be observed in the rat perfused heart depending on the experimental conditions and the amount of PAF (Man et al, 1990). These results may be explained by the existence of two PAF receptor subtypes (Hu et al, 1991). The activation of the first subtype of PAF receptor produces vasodilatation while the activation of the second subtype of PAF receptor produces vasoconstriction.…”

“…It has been proposed that the coronary vasodilator effect of PAF is mediated by LTB4 whereas the vasoconstrictor effect of PAF is mediated by LTC4 and LTD4 (Hu et al, 1991). It is possible that non-specific actions of the PAF antagonists may influence the leukotrienes-mediated vasodilator and vasoconstrictor effects of PAF.…”