Effects of PAF on cardiac function and eicosanoid release in the isolated perfused rat heart: comparison between normotensive and spontaneously hypertensive rats.

Abstract

The aim of this study was (a) in isolated perfused rat heart to characterize the effects of platelet-activating factor (PAF) on coronary flow, ventricular contractility, and eicosanoid release and (b) to determine whether PAF effects are altered in hearts from spontaneously hypertensive rats (SHR). PAF (10(-10)-10(-7) mol) dose-dependently decreased coronary flow and ventricular contractility; concomitantly, coronary effluent concentrations of thromboxane (TX)B2 and prostaglandin F2 alpha (PGF2 alpha) were elevated but not those of prostacyclin. The PAF receptor antagonist WEB 2086 (10(-7)-10(-5) mol/l) concentration-dependently antagonized these PAF effects. In addition; the cyclo-oxygenase inhibitor indomethacin (5 x 10(-5) mol/l) prevented PAF (10(-9)-10(-7) mol) induced eicosanoid release; in the presence of indomethacin PAF caused coronary constriction and ventricular depression only at the highest dose (10(-7) mol) but had no effect at 10(-9) or 10(-8) mol. Moreover, the TXA2 antagonist SQ29,548 (10(-6) mol/l) completely inhibited 10(-8) mol PAF induced ventricular depression but did not effect coronary constriction. In SHR PAF (10(-9)-10(-7) mol) evoked decreases in coronary flow and ventricular contractility did not differ from those in normotensive Wistar-Kyoto rats while PAF induced TXA2 and PGF2 alpha release was markedly enhanced. In addition, decreases in coronary flow and ventricular contractility induced by the TXA2 agonist U 46619 (10(-7) mol/l) were markedly depressed in SHR. We conclude that in isolated perfused rat heart PAF causes coronary constriction and depression of ventricular function mainly indirectly through released TXA2 and/or PGF2 alpha. Moreover, the fact that in SHR the PAF effects on coronary flow and ventricular function are not altered despite markedly enhanced TXA2 and PGF2 alpha release supports the view that in the SHR the receptors mediating TXA2 and/or PGF2 alpha effects are desensitized.