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Cardiovascular Research Advance Access first published online on August 14, 2008
This version [Corrected Proof] published online on September 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn216
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Prostanoid F receptors elicit an inotropic effect in rat left ventricle by enhancing myosin light chain phosphorylation

Jon Riise1,2, Cam H.T. Nguyen1,2, Eirik Qvigstad1,2, Dagny L. Sandnes1, Jan-Bjørn Osnes1,2, Tor Skomedal1,2, Finn Olav Levy1,2,* and Kurt A. Krobert1,2

1 Department of Pharmacology, University of Oslo, Sognsvannsvn. 20, Building A2/A3, PO Box 1057 Blindern, N-0316 Oslo, Norway
2 Center for Heart Failure Research, University of Oslo, 0407 Oslo, Norway

* Corresponding author. Tel: +47 22840237; fax: +47 22840202. E-mail address: f.o.levy{at}medisin.uio.no

Aims: The aims of this study were to determine if the prostanoid F receptor (FPR)-mediated inotropic effect in rat ventricle is mediated by increased phosphorylation of myosin light chain-2 (MLC-2) and to elucidate the signalling pathway(s) activated by FPRs to regulate MLC-2 phosphorylation.

Methods and results: Contractility was measured in left ventricular strips from adult male rats. Strips were also snap-frozen, and changes in the phosphorylation level of both MLC-2 and myosin phosphatase targeting subunit-2 (MYPT-2) were quantified. FPR stimulation with fluprostenol increased contractility by ~100% above basal and increased phosphorylation of both MLC-2 (by ~30%) and MYPT-2 (by ~50%). The FPR-mediated inotropic effect and MLC-2 phosphorylation were reduced by a similar magnitude in the presence of the myosin light chain kinase (MLCK) inhibitor ML-7 (~60–70%) and an inhibitor of Ca2+/calmodulin, W-7 (~35%). Inhibition of Rho-associated kinase by Y-27632 reduced the FPR-mediated inotropic effect and MLC-2 phosphorylation by ~40–45% and MYPT-2 phosphorylation by ~70%. ML-7 and Y-27632 together reduced contractility and MLC-2 phosphorylation by ~70–80%. The FPR-mediated inotropic effect was only modestly affected by high concentrations of the inositol tris-phosphate (IP3) receptor blocker 2-APB, but not by the protein kinase C (PKC) inhibitor bisindolylmaleimide.

Conclusion: The FPR-evoked inotropic effect is mediated by increasing the phosphorylation of MLC-2 through regulation of both MLCK and myosin light chain phosphatase activities. The second messenger IP3 and PKC are unlikely to be involved in the signalling cascade of the FPR-mediated positive inotropic effect. Therefore, FPR signalling mechanism(s) regulating MLC-2 phosphorylation likely extend beyond those classically established for Gq/11-coupled receptors.

KEYWORDS Contractile function; Inotropic agents; Signal transduction; Ventricular function; Calcium sensitization

Time for primary review: 32 days


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