Interaction of vasoactive substances released by platelet-activating factor in the rat perfused heart.
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 (100 pmol) 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 (100 pmol) 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 (5 microM), partially reduced the vasoconstrictor effect of the effluent. Pretreatment of the first heart with indomethacin (2.8 microM) 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, 10 microM) 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.
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Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
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D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology*; D001784:Blood Gas Analysis; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D020024:Leukotriene Antagonists; D010477:Perfusion; D010654:Phenylbutyrates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011188:Potassium / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors; D012964:Sodium / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects; D002722:Chlorobenzenes
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D007213:Indomethacin; D020024:Leukotriene Antagonists; D010654:Phenylbutyrates; D010972:Platelet Activating Factor; D011188:Potassium; D013189:SRS-A; D012964:Sodium; C060893:MK-886; D002722:Chlorobenzenes; C050033:L 649923