[Effect of carvedilol on ryanodine receptor in heart failure].
OBJECTIVE
The release of intracellular stores of Ca(2+) occurs virtually in all types of cells by a means of amplifying external signals that modulate intracellular signaling events. In cardiac myocytes, type 2 ryanodine receptor (RyR(2)) is activated during excitation-contraction (E-C) coupling by Ca(2+)-induced Ca(2+) release (CICR) triggered by Ca(2+) influx across the sarcolemma. The hyperadrenergic state of heart failure results in leaky RyR(2) channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FK506 binding protein, FKBP12.6. Dysregulation of sarcoplasmic reticulum (SR) Ca(2+) release via RyR(2) could contribute to defects in Ca(2+) signaling in failing hearts. Researchers tested the hypothesis that improved cardiac muscle function attributable to beta-AR blockade is associated with restoration of normal RyR(2) channel function in patients with heart failure. The authors aimed to observe change of RyR in junior mouse with HF and the effect of beta-adrenoreceptor blocker on RyR in HF in this experiment.


METHODS
The animal model of congestive heart failure was established by constriction of abdominal aorta. Five weeks old mice were randomly divided into 3 groups: (1) HF group without treatment (n = 20); (2) HF group treated with carvedilol (n = 20); (3) Sham-operated group (n = 20). Carvedilol was administered through direct gastric gavage. After 4 weeks of treatment the high frequency ultrasound was performed. Myocardial SR was fractionated with velocity centrifugation. The time courses of Ca(2+) uptake and leak were determined by fluorescent spectrophotometr.


RESULTS
Compared with the sham-operated group, left ventricular diastolic dimension (LVEDD) (P < 0.05), left ventricular systolic dimension (LVESD), interventricular septal thickness at end-diastole (IVSTd), interventricular septal thickness at end-systole (IVSTs), left ventricular posterior wall thickness at end-diastole (LVPWTd), and left ventricular posterior wall thickness at end-systole (LVPWTs) were all significantly increased (P < 0.01). Ejection fraction (EF) and fractional shortening (FS) were decreased (P < 0.01) in HF group without treatment. LVEDD (P < 0.05), LVESD, IVSTd, IVSTs, LVPWTd and LVPWTs were all prominently decresed (P < 0.01). EF and FS were increased (P < 0.01) in cases of HF treated with carvedilol when compared with HF group without treatment. After adding thapsigargin to the buffer including SR of three groups, there were fewer Ca(2+) leak in sham-operated group and HF group treated with carvedilol than that of HF group without treatment (P < 0.01), while after adding FK506 and thapsigargin together to the buffer including SR of three groups, there were marked Ca(2+) leak in sham-operated group and HF group treated with carvedilol (P < 0.01). However, there was no additional increase in Ca(2+) leak in HF group compared with that of the group where only thapsigargin was added (P > 0.05).


CONCLUSIONS
There is more cardiac Ca(2+) leak in HF. Carvedilol can inhibite Ca(2+) leak by restoring the contactation of FKBP12.6 back to RyR in HF to improve cardiac function and prevent left ventricle from remodeling.
Li
Rong
R
Department of Cardiovascular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
Yi
Qi-jian
QJ
Qian
Yong-ru
YR
Liu
Xiao-yan
XY
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004195:Disease Models, Animal; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D019284:Thapsigargin / Q000494:pharmacology; D014463:Ultrasonography
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D000077261:Carvedilol; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium