Aims: Prostaglandin-modulatory approaches in heart failure patients have not shown beneficial effects in clinical studies.Both treatment with prostaglandins and inhibition ofprostaglandin synthesis have resulted in increased mortality in heart failure patients.Currently, it remains unknown if prostaglandin-mediated effects upon contractility are detrimental or favourable in the failing heart.Therefore, the objectives of this study were to determine ifprostanoids could elicit direct inotropic effects in human ventricle, and determine whether they are modified in failing ventricle.Methods and results: Contractile force was measured in ventricular strips from non-failing or failing human and rat hearts.The ratio of phosphorylated to non-phosphorylated myosin light chain (MLC) 2 was measured by Western blotting in rat myocardial strips, and the levels of prostanoid F receptor (FPR) mRNA and protein were measured by real time-PCR and receptor binding assays.In non-failing human hearts, iloprost and PGE1 evoked a cAMP-independent positive inotropic effect which was absent in failing human hearts.Similarly, the FPR-mediated inotropic effect was reduced by ~50% in failing compared to non-failing rat heart, but the fluprostenol-induced increase of MLC-2 phosphorylation levels was unchanged.FPR-density was significantly reduced by ~40%.Conclusions: Prostanoids may provide inotropic support in non-failing human heart, likely by enhancing myofilament calcium sensitivity through MLC-2 phosphorylation, representing a less energy-demanding mechanism than beta-adrenergic activation of cAMP signalling.Possibly, the significant reduction ofprostanoid-mediated inotropic support observed in both human and rat failing heart may be detrimental.