AT1 receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+ -leak induced by oxidative stress.
BACKGROUND
The Ca(2+) regulatory proteins in the sarcoplasmic reticulum (SR) play a key role in the pathogenesis of heart failure. In the present study the effect of chronic beta-receptor-stimulation on cardiac and SR functions was assessed, with or without angiotensin-II receptor antagonist treatment recently reported to have anti-beta-adrenergic activity.


RESULTS
Rats were treated with isoproterenol with (+) or without (-) candesartan (CAN) and then SR vesicles were isolated from the left ventricular muscle. Both Ca(2+)-uptake and the amount of SR Ca(2+)-ATPase were significantly lower in the CAN (-) group than in the shams, but those were almost normally restored in the CAN (+). Although the level of the protein kinase A (PKA)-phosphorylation of the SR Ca(2+) release channel, known as the ryanodine receptor (RyR2), was elevated in the CAN (-), no Ca(2+)-leak was detected. However, SIN-1 (O(2) (-) donor) induced Ca(2+)-leak in the CAN (-) at a 10-fold lower dose than in the sham and CAN (+). In cardiomyocytes, SIN-1 decreased cell shortening and the peak Ca(2+) transient and prolonged time from peak to 70% decline in CAN (-), again at 10-fold lower dose than in the sham and CAN (+).


CONCLUSIONS
Chronic beta-receptor-stimulation did not induce any Ca(2+)-leak from the SR, whereas Ca(2+)-leak was easily induced when oxidative stress was applied to the PKA-phosphorylated RyR2. Candesartan not only improved Ca(2+)-uptake, but also prevented PKA-phosphorylation, rendering the SR less susceptible to Ca(2+)-leak.
Tokuhisa
Takahiro
T
Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Ube, Japan.
Yano
Masafumi
M
Obayashi
Masakazu
M
Noma
Toshiyuki
T
Mochizuki
Mamoru
M
Oda
Tetsuro
T
Okuda
Shinichi
S
Doi
Masahiro
M
Liu
Jinyao
J
Ikeda
Yasuhiro
Y
Yamamoto
Takeshi
T
Ohkusa
Tomoko
T
Matsuzaki
Masunori
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000633:toxicity; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism*; D007545:Isoproterenol / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D044140:Receptor, Angiotensin, Type 1; D019837:Ryanodine Receptor Calcium Release Channel; D013777:Tetrazoles; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; C081643:candesartan; D002118:Calcium