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Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet-activating factor is mediated by
Insights
Platelet-activating factor (Paf) causes heart problems by releasing leukotriene C4 (LTC4), leading to coronary vasoconstriction. Cyclo-oxygenase products also play a role in Paf-induced decreases in cardiac contractility.
Area of Science:
- Cardiovascular Pharmacology
- Inflammation and Immunology
- Biochemical Signaling Pathways
Background:
- Platelet-activating factor (Paf) is a potent lipid mediator implicated in cardiovascular and inflammatory responses.
- The specific mechanisms by which Paf affects cardiac function and coronary tone, particularly the roles of eicosanoids, require further elucidation.
- Understanding these pathways is crucial for developing targeted therapies for cardiovascular diseases.
Purpose of the Study:
- To investigate the effects of Platelet-activating factor (Paf) on coronary vasoconstriction and cardiac contractility in isolated rat hearts.
- To identify and quantify the specific eicosanoids released in response to Paf.
- To determine the involvement of leukotrienes and cyclo-oxygenase products in Paf-mediated cardiovascular effects.
Main Methods:
- Isolated perfused rat hearts were treated with varying doses of Paf.
- Cardiac effluents were collected and analyzed for leukotriene-like bioactivity and prostanoids (6-keto-PGF1α, PGF2α, PGE2, TXB2) using radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC).
- The effects of inhibitors (indomethacin, diethylcarbamazine, FPL 55712) on Paf-induced responses were assessed.
Main Results:
- Paf induced dose-dependent coronary vasoconstriction and decreased cardiac contractility.
- Paf stimulated the release of leukotriene C4 (LTC4) and leukotriene B4 (LTB4), as well as cyclo-oxygenase products (6-keto-PGF1α, PGF2α, PGE2, TXB2).
- LTC4 was identified as a major mediator of Paf-induced coronary vasoconstriction, while cyclo-oxygenase products were involved in the decrease in cardiac contractility.
Conclusions:
- Leukotriene C4 (LTC4) is primarily responsible for Platelet-activating factor (Paf)-induced coronary vasoconstriction.
- Cyclo-oxygenase products may modulate Paf-induced coronary vasoconstriction and are involved in the reduction of cardiac contractility.
- These findings highlight the complex interplay of eicosanoids in mediating Paf's cardiovascular effects.
Abstract:
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. Platelet-activating factor (0.9 nmol) induced an increase in 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), PGF2 alpha, PGE2 and thromboxane B2 (TXB2) measured by radioimmunoassay (RIA) of cardiac effluents following partial purification using C18 Sep-Paks. 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. The release of cyclo-oxygenase products by Paf was prevented by indomethacin (2.8 microM), markedly attenuated by diethylcarbamazine (7.7 mM) but unaffected by FPL 55712 (1.9 microM)-pretreatment. Furthermore, LTC4 (50 pmol) did not increase the release of the cyclo-oxygenase products measured. The release of LTB4 and LTC4 appeared to be unaffected by indomethacin pretreatment whereas diethylcarbamazine-pretreatment markedly inhibited release. 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. 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.