Effects of exogenous prostaglandins on the release of leukotriene C4-like immunoreactivity and on coronary flow in indomethacin-treated anaphylactic guinea-pig hearts

Abstract

It is known that both vasoconstrictor cyclooxygenase products and sulfidopeptide-containing leukotrienes (LT) contribute to the biphasic coronary constriction observed in isolated perfused anaphylactic guinea-pig hearts. We have now investigated the effects of the cyclooxygenase inhibitor indomethacin and of several exogenous prostaglandins (PG) on the release of LTC4-like immunoreactivity and on various symptoms of cardiac anaphylaxis. Indomethacin decreased basal coronary flow and delayed the onset of coronary vasoconstriction after antigenic challenge. Furthermore, indomethacin inhibited cardiac release of 6-keto-PGF1 alpha and thromboxane (TX) B2 and simultaneously enhanced the antigen-induced release of LTC4-like immunoreactivity significantly. Neither the vasodilators PGE2 and PGI2 nor the vasoconstrictors PGF2 alpha, PGD2 and 11,9-epoxymethano-PGH2, a compound with biological properties similar to TXA2, affected the anaphylactic release of immunoreactive LTC4 in the presence of indomethacin. These results suggest that the indomethacin-induced increase in LT release is not due to inhibition of synthesis of a cyclooxygenase product, which normally curbs anaphylactic release of immunoreactive LTC4. The indomethacin effect may rather be explained by diversion of arachidonic acid metabolism away from fatty acid cyclooxygenase towards the synthesis of lipoxygenase products. Although the various PG did not significantly affect cardiac release of LTC4-like immunoreactivity, they antagonized the anaphylactic coronary constriction. This antagonism may be due to direct effects of the PG on vascular smooth muscle tone as well as to indirect effects on the release of anaphylactic mediators not related to LT like histamine and platelet-activating factor.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…The Table 5 Change in production and release ofcyclo-oxygenase products induced by leukotriene C4 (LTC4) or plateletactivating factor (Paf) in control and FPL 55712-pretreated hearts small inhibitory effect of indomethacin on the Pafinduced coronary vasoconstriction suggests that the predominant influence of cyclo-oxygenase metabolites is vasoconstrictor. In addition, indomethacin pretreatment failed to increase the release of either LTB4 or LTC4 in contrast to observations in guinea-pig cardiac (Aeringhaus et al, 1984) and pulmonary (Engineer et al, 1978) anaphylaxis. However, the release of leukotrienes from chopped lung induced by Paf (Beaubien et al, 1984) and that released from human lung parenchyma by Ca2" ionophore (Sautebin et al, 1985) has been found not to be enhanced by indomethacin pretreatment, suggesting that the enhancing effect of indomethacin may be stimulus-specific.…”

“…Thus, the PGF2., PGE2 and PGI2 released by Paf may reduce the Paf-induced coronary vasoconstriction. There is considerable evidence that the release of TXA2 in the coronary circulation leads to vasoconstriction (Anhut et al, 1978, Allan & Levi, 1981Aeringhaus et al, 1984). The Table 5 Change in production and release ofcyclo-oxygenase products induced by leukotriene C4 (LTC4) or plateletactivating factor (Paf) in control and FPL 55712-pretreated hearts small inhibitory effect of indomethacin on the Pafinduced coronary vasoconstriction suggests that the predominant influence of cyclo-oxygenase metabolites is vasoconstrictor.…”

“…There is considerable evidence that the release of TXA2 in the coronary circulation leads to vasoconstriction (Anhut et al, 1978, Allan & Levi, 1981Aeringhaus et al, 1984). The small inhibitory effect of indomethacin on the Pafinduced coronary vasoconstriction suggests that the predominant influence of cyclo-oxygenase metabolites is vasoconstrictor.…”

Inhibition of leukotriene release in anaphylactic guinea‐pig hearts by a 5‐lipoxygenase inhibitor, CGS 8515

“…This is in apparent agreement with the previous observation that prostaglandin F2, (PGF2.) completely suppressed the antigen-induced arrhythmias while PGE2 and PGI2 decreased the incidence of arrhythmias in guinea-pig anaphylactic hearts (Aehringhaus et al, 1984). Thus, the enhancement in the anaphylactic release of LTC4 when sensitized hearts were challenged in the presence of indomethacin seen in the present experiments suggests two possibilities: firstly, cyclo-oxygenase products may exert a direct negative feedback on the anaphylactic release of leukotrienes and secondly, blocking the cyclo-oxygenase pathway resulted in a diversion of arachidonic acid metabolism away from cyclo-oxygenase towards the synthesis of lipoxygenase products.…”

“…Various mediators have been implicated in cardiac anaphylaxis. Technological advances during the past decade have revealed that lipoxygenation of arachidonic acid (AA) gives rise to a number of products with diverse biological activities and in particular, the discovery of leukotrienes as active constituents of SRS-A released immunologically from guinea-pig hearts (Aehringhaus et al, 1984) has enabled us to elucidate further the mediators involved in cardiac anaphylaxis.…”