Platelet-activating factor-induced coronary constriction in the isolated perfused guinea pig heart and antagonistic effects of the PAF antagonist WEB 2086.
Platelet-activating factor (PAF) has been called an important mediator of cardiovascular shock due to immunological reactions including anaphylaxis and endotoxic reactions. According to previous reports, PAF dose-dependently decreases ventricular contractility and coronary flow rates. Diverse mechanisms of the PAF-induced cardiodepressive effects have been postulated. Besides direct receptor stimulation, the release of other vasoactive mediators such as the eicosanoids has been reported. In this study, an attempt was made to characterize the direct PAF effects on the coronary circulation of the isolated constant pressure perfused guinea pig heart. A further objective was to evaluate whether PAF releases the potent vasoconstrictor thromboxane A2 in biologically relevant amounts. A continuous intracoronary infusion of the selective PAF antagonist WEB 2086 (3.7 x 10(-9) mol/min and 1.1 x 10(-7) mol/min, related to coronary flow rates of 1 ml/min) induced a dose-dependent vasodilation resulting in final perfusate concentrations of 2.5 x 10(-6) mol/l and 5.5 x 10(-5) mol/l, respectively. An intracoronary bolus injection of PAF in a submaximal dose (2.3 x 10(-10) mol, related to coronary flow rates of 1 ml/min) markedly decreased coronary flow rates and produced a significant increase in immunoreactive thromboxane B2 levels in the coronary effluent. WEB 2086 antagonized the PAF-induced coronary constriction in a dose-dependent manner. In addition, thromboxane release ceased entirely. In contrast, the selective thromboxane A2 receptor antagonist BM 13505 (0.9 x 10(-4) mol/1) attenuated the initial phase of coronary constriction only moderately. It is therefore concluded that the detected thromboxane release plays a subordinate role in the PAF-mediated coronary effects.
Felix
S B
SB
First Department of Medicine, Technische Universität München, Klinikum rechts der Isar, F.R.G.
Steger
A
A
Baumann
G
G
Busch
R
R
Ochsenfeld
G
G
Berdel
W E
WE
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D010477:Perfusion; D010648:Phenylacetates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D001381:Azepines; D010648:Phenylacetates; D010972:Platelet Activating Factor; D013449:Sulfonamides; D014230:Triazoles; C052518:WEB 2086; D013928:Thromboxane A2; C051762:daltroban