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Prostaglandin E1 facilitates inotropic effects of 5-HT4 serotonin receptors and β-adrenoceptors in failing human heart

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Abstract

Prostaglandins have displayed both beneficial and detrimental effects in clinical studies in patients with severe heart failure. Prostaglandins are known to increase cardiac output, but the mechanism is not clarified. Here, we tested the hypothesis that prostaglandins can increase contractility in human heart by amplifying cAMP-dependent inotropic responses. Contractility was measured ex vivo in isolated left ventricular strips and phosphodiesterase (PDE) and adenylyl cyclase (AC) activity was measured in homogenates or membranes from failing human left ventricles. PGE1 (1 µM) alone did not modify contractility, but given prior, amplified maximal serotonin (5-HT)-evoked (10 µM) contractile responses mediated by 5-HT4 receptors several fold (24 ± 7 % with PGE1 vs. 3 ± 2 % above basal with 5-HT alone). The 5-HT4-mediated inotropic response was amplified by the PDE3 inhibitor cilostamide and further amplified in combination with PGE1 (26 ± 6 vs. 56 ± 12 % above basal). PGE1 reduced the time to reach 90 % of both the maximal 5-HT- and isoproterenol-evoked inotropic response compared to 5-HT or isoproterenol alone. PGE1 did not modify PDE activity in the homogenate, either alone or when given simultaneously with PDE3 and/or PDE4 inhibitors. Neither 5-HT- nor isoproterenol-stimulated AC activity was significantly amplified by PGE1. Sensitivity of ventricular strips to Ca2+ was not enhanced in the presence of PGE1. Our results show that PGE1 can enhance cAMP-mediated responses in failing human left ventricle, through a mechanism independent of PDE inhibition, amplification of AC activity or increasing sensitivity to calcium. This effect of PGE1 possibly contributes to the increase of cardiac output, independent of decreased afterload, observed after prostaglandin administration in humans.

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Acknowledgments

This work was supported by The Norwegian Council on Cardiovascular Disease, The Research Council of Norway, Stiftelsen Kristian Gerhard Jebsen, Anders Jahre’s Foundation for the Promotion of Science, The Family Blix Foundation, The Simon-Fougner-Hartmann Family Foundation, South-Eastern Norway Regional Health Authority and foundations at the University of Oslo.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Sognsvannsvn. 20, Bldg. A2/A3, P.O. Box 1057, Blindern, 0316, Oslo, Norway

    Jon Riise, Øivind Ørstavik, Eirik Qvigstad, Jan-Bjørn Osnes, Tor Skomedal, Finn Olav Levy & Kurt A. Krobert

  2. K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, University of Oslo, Oslo, Norway

    Jon Riise, Øivind Ørstavik, Eirik Qvigstad, Christen P. Dahl, Jan-Bjørn Osnes, Tor Skomedal, Finn Olav Levy & Kurt A. Krobert

  3. Department of Cardiology, Oslo University Hospital Rikshospitalet, 0027, Oslo, Norway

    Christen P. Dahl

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  1. Jon Riise
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Correspondence to Finn Olav Levy.

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Riise, J., Ørstavik, Ø., Qvigstad, E. et al. Prostaglandin E1 facilitates inotropic effects of 5-HT4 serotonin receptors and β-adrenoceptors in failing human heart. Basic Res Cardiol 107, 295 (2012). https://doi.org/10.1007/s00395-012-0295-z

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