Interventricular differences in β-adrenergic responses in the canine heart
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Interventricular differences in β-adrenergic responses in the canine heart : role of phosphodiesterases. / Molina, Cristina E; Johnson, Daniel M; Mehel, Hind; Spätjens, Roel L H M G; Mika, Delphine; Algalarrondo, Vincent; Slimane, Zeineb Haj; Lechêne, Patrick; Abi-Gerges, Najah; van der Linde, Henk J; Leroy, Jérôme; Volders, Paul G A; Fischmeister, Rodolphe; Vandecasteele, Grégoire.
In: J AM HEART ASSOC, Vol. 3, No. 3, 05.06.2014, p. e000858.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Interventricular differences in β-adrenergic responses in the canine heart
T2 - role of phosphodiesterases
AU - Molina, Cristina E
AU - Johnson, Daniel M
AU - Mehel, Hind
AU - Spätjens, Roel L H M G
AU - Mika, Delphine
AU - Algalarrondo, Vincent
AU - Slimane, Zeineb Haj
AU - Lechêne, Patrick
AU - Abi-Gerges, Najah
AU - van der Linde, Henk J
AU - Leroy, Jérôme
AU - Volders, Paul G A
AU - Fischmeister, Rodolphe
AU - Vandecasteele, Grégoire
N1 - © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
PY - 2014/6/5
Y1 - 2014/6/5
N2 - 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.METHODS AND 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.CONCLUSION: 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.
AB - 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.METHODS AND 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.CONCLUSION: 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.
KW - Animals
KW - Calcium
KW - Cyclic AMP
KW - Dogs
KW - Female
KW - Heart
KW - Heart Ventricles
KW - Myocytes, Cardiac
KW - Patch-Clamp Techniques
KW - Phosphoric Diester Hydrolases
KW - Receptors, Adrenergic, beta
KW - Sarcomeres
KW - Ventricular Function
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1161/JAHA.114.000858
DO - 10.1161/JAHA.114.000858
M3 - SCORING: Journal article
C2 - 24904016
VL - 3
SP - e000858
JO - J AM HEART ASSOC
JF - J AM HEART ASSOC
SN - 2047-9980
IS - 3
ER -