Interventricular differences in β-adrenergic responses in the canine heart

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 -