title: Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction.
abstract: BACKGROUND
  Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.
  
  
  OBJECTIVE
  To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.
  
  
  RESULTS
  Pharmacological inhibition of phosphodiesterase 2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor-mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.
  
  
  CONCLUSIONS
  Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Christiane
authors: C
authors: Vettel
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Marta
authors: M
authors: Lindner
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Matthias
authors: M
authors: Dewenter
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Kristina
authors: K
authors: Lorenz
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Constanze
authors: C
authors: Schanbacher
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Merle
authors: M
authors: Riedel
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Simon
authors: S
authors: Lämmle
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Simone
authors: S
authors: Meinecke
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Fleur E
authors: FE
authors: Mason
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Samuel
authors: S
authors: Sossalla
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Andreas
authors: A
authors: Geerts
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Michael
authors: M
authors: Hoffmann
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Frank
authors: F
authors: Wunder
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Fabian J
authors: FJ
authors: Brunner
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Thomas
authors: T
authors: Wieland
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Hind
authors: H
authors: Mehel
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Sarah
authors: S
authors: Karam
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Patrick
authors: P
authors: Lechêne
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Jérôme
authors: J
authors: Leroy
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Grégoire
authors: G
authors: Vandecasteele
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Michael
authors: M
authors: Wagner
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
authors: Rodolphe
authors: R
authors: Fischmeister
authors: From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.). ali.el-armouche@tu-dresden.de rodolphe.fischmeister@inserm.fr.
authors: Ali
authors: A
authors: El-Armouche
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000378:metabolism*; D002395:Catecholamines / Q000633:toxicity; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004285:Dogs; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D014227:Triazines / Q000494:pharmacology
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D002316:Cardiotonic Agents; D002395:Catecholamines; D007093:Imidazoles; D014227:Triazines; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D007545:Isoproterenol
keywords: cardiac arrhythmia; catecholamine; cyclic GMP-stimulated phosphodiesterase; heart rate; myocardial contraction