Role of platelet-activating factor (PAF) in oxygen radical-induced cardiac dysfunction.
Several studies established the role of oxygen radicals in cardiac alterations occurring during ischemia and reperfusion. Recently, platelet-activating factor (PAF), a phospholipid mediator of inflammation, was also implicated in ischemia-reperfusion injury. The present study was performed to evaluate whether biosynthesis of PAF may mediate the mechanical and electrical alterations induced by perfusion with dihydroxyfumaric acid (DHF; 1 mM), a free radical-generating compound, in guinea pig isolated perfused heart and isolated atrium. The results obtained indicate that DHF induces an intracoronary production of PAF (DHF-perfused hearts = 43.1 +/- 3.9 pg PAF; saline-perfused control hearts = PAF undetectable) and electrical and mechanical alterations in both isolated heart and atrium. These effects were shown to be dependent on superoxide (O2-) generation, because they were completely prevented by superoxide dismutase (10 mM), and were absent when DHF's ability to produce O2- was exhausted in solution. The role of PAF in mediating oxygen radical-induced electrical and mechanical alterations was established by pretreatment of cardiac preparations with WEB 2170 (0.1-10 microM), a specific PAF-receptor antagonist devoid of any direct antioxidant activity. At the concentration of 3 microM, WEB 2170 abrogated almost completely all the cardiac effect of DHF. These results suggest that PAF may act as secondary mediator of oxygen radicals in the heart.
Alloatti
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G
Laboratorio di Fisiologia Generale, Ospedale S. Luigi Gonzaga, Orbassano, Italy.
Montrucchio
G
G
Camussi
G
G
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D005609:Free Radicals; D005650:Fumarates / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000633:toxicity*; D013482:Superoxide Dismutase; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D005609:Free Radicals; D005650:Fumarates; D010972:Platelet Activating Factor; D017382:Reactive Oxygen Species; D014230:Triazoles; C005998:dihydroxyfumarate; C063964:bepafant; D013482:Superoxide Dismutase