title: Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases.
abstract: BACKGROUND
  RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β-adrenergic (β-AR) responsiveness is unknown. In this study, we examine whether β-AR response and signaling differ in right (RV) versus left (LV) ventricles.
  
  
  RESULTS
  Sarcomere shortening, Ca(2+) transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes. Intracellular [cAMP] and PKA activity were measured by live cell imaging using FRET-based sensors. Isoproterenol increased sarcomere shortening ≈10-fold and Ca(2+)-transient amplitude ≈2-fold in LV midmyocytes (LVMs) versus ≈25-fold and ≈3-fold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2-fold higher β-AR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, β-AR regulation of ICa,L and IKs were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the β-AR regulation of cytoplasmic [cAMP], and the difference between LVMs and RVMs was abolished by PDE3 inhibition and attenuated by PDE4 inhibition. Finally LV and RV intracavitary pressures were recorded in anesthetized beagle dogs. A bolus injection of isoproterenol increased RV dP/dtmax≈5-fold versus 3-fold in LV.
  
  
  CONCLUSIONS
  Canine RV and LV differ in their β-AR response due to intrinsic differences in myocyte β-AR downstream signaling. Enhanced β-AR responsiveness of the RV results from higher cAMP elevation in the cytoplasm, due to a decreased degradation by PDE3 and PDE4 in the RV compared to the LV.
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Molina
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, 6202 AZ, Maastricht, The Netherlands (D.M.J., R.G.S., P.A.V.).
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Johnson
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Hind
authors.initials: H
authors.lastname: Mehel
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, 6202 AZ, Maastricht, The Netherlands (D.M.J., R.G.S., P.A.V.).
authors.forename: Roel L H M G
authors.initials: RL
authors.lastname: Spätjens
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Delphine
authors.initials: D
authors.lastname: Mika
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Algalarrondo
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Zeineb Haj
authors.initials: ZH
authors.lastname: Slimane
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Lechêne
authors.affiliation: Department of Translational Safety, DrugSafety and Metabolism, AstraZeneca R&D Innovative Medicines and Early Development, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK (N.A.G.).
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.affiliation: Global Safety Research, Preclinical Development & Safety, Discovery Sciences, Janssen Research & Development, Beerse, Belgium (H.J.L.).
authors.forename: Henk J
authors.initials: HJ
authors.lastname: van der Linde
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leroy
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, 6202 AZ, Maastricht, The Netherlands (D.M.J., R.G.S., P.A.V.).
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vandecasteele
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D004285:Dogs; D005260:Female; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology; D018408:Patch-Clamp Techniques; D010727:Phosphoric Diester Hydrolases; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012518:Sarcomeres / Q000502:physiology; D016276:Ventricular Function / Q000502:physiology*
chemical_list: D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D002118:Calcium
keywords: cAMP; dog; heart ventricles; phosphodiesterases; β‐adrenergic stimulation