Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet‐activating factor is mediated by leukotriene C₄

Abstract

1 Platelet-activating factor (Paf, 0.04-4.50 nmol) dose-dependently induced coronary vasoconstriction and decreased cardiac contractility in rat, isolated perfused hearts and concomitantly released leukotriene-like bioactivity into the cardiac effluent.2 Platelet-activating factor (0.9 nmol) induced an increase in 6-keto-prostaglandin Fl (6-keto-PGFI.), PGF2., PGE2 and thromboxane B2 (TXB2) measured by radioimmunoassay (RIA) of cardiac effluents following partial purification using C18 Sep-Paks. 3 The leukotriene-like bioactivity released by Paf was identified as leukotriene C4 (LTC4) using a combination of isolation on reverse phase-h.p.l.c. (r.p.h.p.l.c.) and quantitation by RIA. In addition, LTB4 was also identified by r.p.h.p.l.c. and the levels, determined by RIA, were within the range having biological activity. 4 The release ofcyclo-oxygenase products by Pafwas prevented by indomethacin (2.8 pM), markedly attenuated by diethylcarbamazine (7.7mM) but unaffected by FPL 55712 (1.9 pM)-pretreatment. Furthermore, LTC4 (50 pmol) did not increase the release of the cyclo-oxygenase products measured. 5 The release of LTB4 and LTC4 appeared to be unaffected by indomethacin pretreatment whereas diethylcarbamazine-pretreatment markedly inhibited release. 6 The coronary vasoconstriction induced by Paf (0.9 nmol) was attenuated by pretreatment with indomethacin or diethylcarbamazine, whereas FPL 55712 caused a marked inhibition of the response. In contrast, the decrease in cardiac contractility was prevented by indomethacin or diethylcarbamazine and unaffected by FPL 55712 pretreatment. 7 It is concluded that LTC4 may be largely responsible for the coronary vasoconstriction induced by Paf with cyclo-oxygenase products having a possible modulatory role whereas the latter appear to be involved in the Paf-induced decrease in cardiac contractility.

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

“…Also,6 indomethacin blocked the coronary constriction produced by 1 + 4a 10 intracoronary injection of PAF in the pig heart (Feuerstein et al, 1984 response of PAF and are contrary to previous results. This can be due to the differences in the perfusion pressure in our study from those of Piper & Stewart (1986. The higher reatment with starting perfusion pressure used in the present study may be .e decrease in more susceptible to demonstrating the vasodilator response of 100 pmol (Man et al, 1990) than the lower perfusion pressure used preand 9 in the viously.…”

“…This included LTB4, LTC4 and LTD4 (Piper & Stewart, 1986). However, the source for the production of these leukotrienes by PAF has not been fully identified.…”

“…In previous studies, the leukotriene antagonist FPL-55712, was shown to attenuate the vasocons-C4 and LTD4 trictor response following injections of PAF (Feuerstein et al., CM FR-900452. 1984;Piper & Stewart, 1986;Fiedler et al, 1987). However, not affect the the vasodilator effect, when observed, was not altered by FPL-)Opmol LTC4 55712 (Feuerstein et al, 1984;Fiedler et al, 1987 (Piper & Stewart, 1986; us to examine Man et al, 1990) ts, Specific binding of radiolabelled PAF was first demonn the coronary strated in platelets (Valone et al, 1982;Hwang et al, 1983) and subsequently demonstrated in a number of tissues (see review of Braquet et al, 1987).…”

“…However, the results of these studies are diverse. PAF was shown to cause vasoconstriction in the guinea-pig perfused heart (Levi et al, 1984;Piper & Stewart, 1987) and in the rat perfused heart (Piper & Stewart, 1986). In contrast, intracoronary injection of PAF to anaesthetized dogs produced only increases in coronary flow and this effect was reduced after the removal of circulating platelets (Jackson et al, 1986).…”

“…The studies of Piper & Stewart (1986 clearly identified the presence of 6-keto-prostaglandin Fg (6-keto-PGFi) thromboxane B2 and leukotriene-like bioactivity in the effluent of the perfused rat and guinea-pig hearts after PAF administration. However, only a vasoconstrictor response was observed in these studies.…”