Abi-Gerges A, Richter W, Lefebvre F, Mateo P, Varin A, Heymes C, Samuel J-L, Lugnier C, Conti M, Fischmeister R, Vandecasteele G (2009) Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on β-adrenergic cAMP signals. Circ Res 105:784–792. https://doi.org/10.1161/CIRCRESAHA.109.197947

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ajiro Y, Hagiwara N, Katsube Y, Sperelakis N, Kasanuki H (2002) Levosimendan increases L-type Ca2+ current via phosphodiesterase-3 inhibition in human cardiac myocytes. Eur J Pharmacol 435:27–33. https://doi.org/10.1016/s0014-2999(01)01569-2

Article  PubMed  CAS  Google Scholar 

Berk E, Christ T, Schwarz S, Ravens U, Knaut M, Kaumann AJ (2016) In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias. Br J Pharmacol 173:2478–2489. https://doi.org/10.1111/bph.13525

Article  PubMed  PubMed Central  CAS  Google Scholar 

Bethke T, Meyer W, Schmitz W, Scholz H, Wenzlaff H, Armah BI, Brückner R, Raap A (1993) High selectivity for inhibition of phosphodiesterase III and positive inotropic effects of MCI-154 in guinea pig myocardium. J Cardiovasc Pharmacol 21:847–855. https://doi.org/10.1097/00005344-199306000-00001

Article  PubMed  CAS  Google Scholar 

Bokník P, Neumann J, Kaspareit G, Schmitz W, Scholz H, Vahlensieck U, Zimmermann N (1997) Mechanisms of the contractile effects of levosimendan in the mammalian heart. J Pharmacol Exp Ther 280:277–283

PubMed  Google Scholar 

Boknik P, Drzewiecki K, Eskandar J, Gergs U, Grote-Wessels S, Fabritz L, Kirchhof P, Müller FU, Stümpel F, Schmitz W, Zimmermann N, Kirchhefer U, Neumann J (2018) Phenotyping of mice with heart specific overexpression of A2A-adenosine receptors: evidence for cardioprotective effects of A2A-adenosine receptors. Front Pharmacol 9:13. https://doi.org/10.3389/fphar.2018.00013

Article  PubMed  PubMed Central  CAS  Google Scholar 

Brunkhorst D, der Leyen H, Meyer W, Nigbur R, Schmidt-Schumacher C, Scholz H (1989) Relation of positive inotropic and chronotropic effects of pimobendan, UD-CG 212 Cl, milrinone and other phosphodiesterase inhibitors to phosphodiesterase III inhibition in guinea-pig heart. Naunyn Schmiedebergs Arch Pharmacol 339:575–583. https://doi.org/10.1007/BF00167264

Article  PubMed  CAS  Google Scholar 

Calamera G, Moltzau LR, Levy FO, Andressen KW (2022) Phosphodiesterases and compartmentation of cAMP and cGMP signaling in regulation of cardiac contractility in normal and failing hearts. Int J Mol Sci 23:1. https://doi.org/10.3390/ijms23042145

Article  CAS  Google Scholar 

Danielsen W, der Leyen H, Meyer W, Neumann J, Schmitz W, Scholz H, Starbatty J, Stein B, Döring V, Kalmár P (1989) Basal and isoprenaline-stimulated cAMP content in failing versus nonfailing human cardiac preparations. J Cardiovasc Pharmacol 14:171–173. https://doi.org/10.1097/00005344-198907000-00026

Article  PubMed  CAS  Google Scholar 

Derici MK, Sadi G, Cenik B, Güray T, Demirel-Yilmaz E (2019) Differential expressions and functions of phosphodiesterase enzymes in different regions of the rat heart. Eur J Pharmacol 844:118–129. https://doi.org/10.1016/j.ejphar.2018.12.002

Article  PubMed  CAS  Google Scholar 

Edes I, Kiss E, Kitada Y, Powers FM, Papp JG, Kranias EG, Solaro RJ (1995) Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res 77:107–113. https://doi.org/10.1161/01.res.77.1.107

Article  PubMed  CAS  Google Scholar 

Endoh M (2015) Does levosimendan act as a Ca2+ sensitizer or PDE3 inhibitor?: Commentary on Orstavik et al., Br J Pharmacol 171: 5169–5181. Br J Pharmacol 172:4594–4596. https://doi.org/10.1111/bph.12649

Article  PubMed  PubMed Central  CAS  Google Scholar 

Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP (1987) Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75:331–339. https://doi.org/10.1161/01.cir.75.2.331

Article  PubMed  CAS  Google Scholar 

Galindo-Tovar A, Kaumann AJ (2008) Phosphodiesterase-4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (-)-adrenaline mediated through mouse cardiac beta(1)-adrenoceptors. Br J Pharmacol 153:710–720. https://doi.org/10.1038/sj.bjp.0707631

Article  PubMed  CAS  Google Scholar 

Gergs U, Boknik P, Schmitz W, Simm A, Silber R-E, Neumann J (2009) A positive inotropic effect of adenosine in cardiac preparations of right atria from diseased human hearts. Naunyn Schmiedebergs Arch Pharmacol 379:533–540. https://doi.org/10.1007/s00210-008-0374-8

Article  PubMed  CAS  Google Scholar 

Gergs U, Böckler A, Ebelt H, Hauptmann S, Keller N, Otto V, Pönicke K, Schmitz W, Neumann J (2013) Human 5-HT4 receptor stimulation in atria of transgenic mice. Naunyn Schmiedebergs Arch Pharmacol 386:357–367. https://doi.org/10.1007/s00210-013-0831-x

Article  PubMed  CAS  Google Scholar 

Gergs U, Fahrion CM, Bock P, Fischer M, Wache H, Hauptmann S, Schmitz W, Neumann J (2017) Evidence for a functional role of calsequestrin 2 in mouse atrium. Acta Physiol (oxf) 219:669–682. https://doi.org/10.1111/apha.12766

Article  PubMed  CAS  Google Scholar 

Gergs U, Trapp T, Bushnaq H, Simm A, Silber R-E, Neumann J (2019a) Age-dependent protein expression of serine/threonine phosphatases and their inhibitors in the human cardiac atrium. Adv Med 2019:2675972. https://doi.org/10.1155/2019/2675972

Article  PubMed  PubMed Central  Google Scholar 

Gergs U, Bernhardt G, Buchwalow IB, Edler H, Fröba J, Keller M, Kirchhefer U, Köhler F, Mißlinger N, Wache H, Neumann J (2019b) Initial characterization of transgenic mice overexpressing human histamine H2 receptors. J Pharmacol Exp Ther 369:129–141. https://doi.org/10.1124/jpet.118.255711

Article  PubMed  CAS  Google Scholar 

Haikala H (1995) Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 27:1859–1866. https://doi.org/10.1016/0022-2828(95)90009-8

Article  PubMed  CAS  Google Scholar 

Haikala H (1997) The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res 34:536–546. https://doi.org/10.1016/s0008-6363(97)00057-6

Article  PubMed  CAS  Google Scholar 

Hamstra SI, Whitley KC, Baranowski RW, Kurgan N, Braun JL, Messner HN, Fajardo VA (2020) The role of phospholamban and GSK3 in regulating rodent cardiac SERCA function. Am J Physiol Cell Physiol 319:C694–C699. https://doi.org/10.1152/ajpcell.00318.2020

Article  PubMed  CAS  Google Scholar 

Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H (1998) Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 98:2141–2147. https://doi.org/10.1161/01.cir.98.20.2141

Article  PubMed  CAS  Google Scholar 

Kaheinen P, Pollesello P, Hertelendi Z, Borbély A, Szilágyi S, Nissinen E, Haikala H, Papp Z (2006) Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+-sensitizing effect but not to stereoselective phosphodiesterase inhibition. Basic Clin Pharmacol Toxicol 98:74–78. https://doi.org/10.1111/j.1742-7843.2006.pto_231.x

Article  PubMed  CAS  Google Scholar 

Maack C, Eschenhagen T, Hamdani N, Heinzel FR, Lyon AR, Manstein DJ, Metzger J, Papp Z, Tocchetti CG, Yilmaz MB, Anker SD, Balligand J-L, Bauersachs J, Brutsaert D, Carrier L, Chlopicki S, Cleland JG, de Boer RA, Dietl A, Fischmeister R, Harjola V-P, Heymans S, Hilfiker-Kleiner D, Holzmeister J, de Keulenaer G, Limongelli G, Linke WA, Lund LH, Masip J, Metra M, Mueller C, Pieske B, Ponikowski P, Ristić A, Ruschitzka F, Seferović PM, Skouri H, Zimmermann WH, Mebazaa A (2019) Treatments targeting inotropy. Eur Heart J 40:3626–3644. https://doi.org/10.1093/eurheartj/ehy600

Article  PubMed  CAS  Google Scholar 

Molenaar P, Christ T, Hussain RI, Engel A, Berk E, Gillette KT, Chen L, Galindo-Tovar A, Krobert KA, Ravens U, Levy FO, Kaumann AJ (2013) PDE3, but not PDE4, reduces β1 - and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. Br J Pharmacol 169:528–538. https://doi.org/10.1111/bph.12167

Article  PubMed  PubMed Central  CAS  Google Scholar 

Molina CE, Leroy J, Richter W, Xie M, Scheitrum C, Lee I-O, Maack C, Rucker-Martin C, Donzeau-Gouge P, Verde I, Llach A, Hove-Madsen L, Conti M, Vandecasteele G, Fischmeister R (2012) Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol 59:2182–2190. https://doi.org/10.1016/j.jacc.2012.01.060

Article  PubMed  CAS  Google Scholar 

Nankervis R, Lues I, Brown L (1994) Calcium sensitization as a positive inotropic mechanism in diseased rat and human heart. J Cardiovasc Pharmacol 24:612–617. https://doi.org/10.1097/00005344-199410000-00012

Article  PubMed  CAS  Google Scholar 

Neumann J, Scholz H, Döring V, Schmitz W, Meyerinck L, Kalmár P (1988) Increase in myocardial Gi-proteins in heart failure. The Lancet 332:936–937. https://doi.org/10.1016/s0140-6736(88)92601-3

Article  Google Scholar 

Neumann J, Bokník P, Schmitz W, Scholz H, Zimmermann N (1995) Comparison of the stereoselective effects of a thiadiazinone derivative on contractile parameters and protein phosphorylation in the mammalian ventricle. J Cardiovasc Pharmacol 25:789–793. https://doi.org/10.1097/00005344-199505000-00015

Article  PubMed  CAS  Google Scholar 

Neumann J, Eschenhagen T, Grupp IL, Haverich A, Herzig JW, Hirt S, Kalmár P, Schmitz W, Scholz H, Stein B, Wenzlaff H, Zimmermann N (1996) Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium. J Pharmacol Exp Ther 277:1579–1585

PubMed  CAS  Google Scholar 

Neumann J, Boknik P, Matherne GP, Lankford A, Schmitz W (2003) Pertussis toxin sensitive and insensitive effects of adenosine and carbachol in murine atria overexpressing A(1)-adenosine receptors. Br J Pharmacol 138:209–217. https://doi.org/10.1038/sj.bjp.0705012

Article  PubMed  PubMed Central