title: Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium.
abstract: Prostanoid-modulatory approaches in heart failure patients have displayed effects which may seem to be mutually incompatible. Both treatment with prostanoids and inhibition of prostanoid synthesis have resulted in increased mortality in heart failure patients. Currently, it is unknown if prostanoids mediate contractile effects in failing human heart and if this can explain some of the clinical effects seen after prostanoid modulatory treatments. Therefore, the objectives of this study were to determine if prostanoids could elicit direct inotropic responses in human ventricle, and if so to determine if they are modified in failing ventricle. Contractile force was measured in left ventricular strips from non-failing or failing human and rat hearts. The ratio of phosphorylated to non-phosphorylated myosin light chain 2 (MLC-2) was measured by Western blotting in myocardial strips, and the levels of prostanoid FP receptor mRNA and protein were measured in rat by real-time RT-PCR and receptor binding assays. In non-failing human hearts, prostanoids evoked a positive inotropic effect and an increase of MLC-2 phosphorylation which was absent in failing human hearts. In failing rat heart, the prostanoid FP receptor-mediated inotropic response and prostanoid FP receptor-density was reduced by ~40-50% compared to non-failing rat heart. Prostanoids mediate a sustained positive inotropic response in non-failing heart, which appears to be down regulated in failing heart. The pathophysiological significance of changes in prostanoid-mediated inotropic support in the failing heart remains to be determined.
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Jon
authors.initials: J
authors.lastname: Riise
authors.forename: Cam H T
authors.initials: CH
authors.lastname: Nguyen
authors.forename: Rizwan I
authors.initials: RI
authors.lastname: Hussain
authors.forename: Christen P
authors.initials: CP
authors.lastname: Dahl
authors.forename: Maren S
authors.initials: MS
authors.lastname: Ege
authors.forename: Jan-Bjørn
authors.initials: JB
authors.lastname: Osnes
authors.forename: Tor
authors.initials: T
authors.lastname: Skomedal
authors.forename: Dagny L
authors.initials: DL
authors.lastname: Sandnes
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Krobert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D024722:Cardiac Myosins / Q000502:physiology; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D018994:Myosin Light Chains / Q000502:physiology; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000502:physiology*; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D018994:Myosin Light Chains; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C107184:myosin light chain 2; C034671:prostaglandin F2alpha receptor; C006326:fluprostenol; D024722:Cardiac Myosins; D000527:Alprostadil; D016285:Iloprost