Impaired β-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure.
Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca2+ homeostatic and molecular mechanisms causing the blunted β-adrenergic (β-AR) response in HF.We induced HF by tachypacing in sheep; intracellular Ca2+ concentration was measured in voltage-clamped ventricular myocytes. In HF, Ca2+ transient amplitude and peak L-type Ca2+ current (ICa-L) were reduced (to 70 ± 11% and 50 ± 3.7% of control, respectively, P <0.05) whereas sarcoplasmic reticulum (SR) Ca2+ content was unchanged. β-AR stimulation with isoprenaline (ISO) increased Ca2+ transient amplitude, ICa-L and SRCa2+ content in both cell types; however, the response of HF cells was markedly diminished (P <0.05).Western blotting revealed an increase in protein phosphatase levels (PP1, 158 ± 17% and PP2A, 188 ± 34% of control, P <0.05) and reduced phosphorylation of phospholamban in HF (Ser16, 30 ± 10% and Thr17, 41 ± 15% of control, P <0.05). The β-AR receptor kinase GRK-2 was also increased in HF (173 ± 38% of control, P <0.05). In HF, activation of adenylyl cyclase with forskolin rescued the Ca2+ transient, SR Ca2+ content and SR Ca2+ uptake rate to the same levels as control cells in ISO. In conclusion, the reduced responsiveness of the myocardium to β-AR agonists in HF probably arises as a consequence of impaired phosphorylation of key intracellular proteins responsible for regulating the SR Ca2+ content and therefore failure of the systolic Ca2+ transient to increase appropriately during β-AR stimulation.
Unit of Cardiac Physiology, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9NT, UK.
Sarah J
SJ
Briston
Jessica L
JL
Caldwell
Margaux A
MA
Horn
Jessica D
JD
Clarke
Mark A
MA
Richards
David J
DJ
Greensmith
Helen K
HK
Graham
Mark C S
MC
Hall
David A
DA
Eisner
Katharine M
KM
Dibb
Andrew W
AW
Trafford
D000818:Animals; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling / Q000502:physiology*; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012756:Sheep; D017180:Tachycardia, Ventricular / Q000150:complications / Q000503:physiopathology*
D011943:Receptors, Adrenergic, beta
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