Probucol attenuates atrial autonomic remodeling in a canine model of atrial fibrillation produced by prolonged atrial pacing.
BACKGROUND
We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation (AF). To test the hypothesis, we examined whether the antioxidant and anti-inflammatory treatment with probucol attenuates atrial autonomic remodeling in a canine model of AF produced by prolonged rapid right atrial pacing.


METHODS
Twenty-one dogs were divided into a sham-operated group, a control group and a probucol group. Dogs in the control group and probucol group underwent right atrial pacing at 400 beats per minute for 6 weeks, and those in the probucol group received probucol 1 week before rapid atrial pacing until pacing stopped. After 6-week rapid atrial pacing, general properties including left atrial structure and function, atrial hemodynamics and the inducibility and duration of AF were measured in all the groups. Atrial oxidative stress markers and serum C-reactive protein (CRP) concentration were estimated. The degree of nerve sprouting and sympathetic innervation at the right atrial anterior wall (RAAW) and the left atrial anterior wall (LAAW) were quantified by immunohistochemistry, atrial norepinephrine contents were also detected. Atrial beta-nerve growth factor (beta-NGF) mRNA and protein expression at the RAAW and LAAW were assessed by real-time quantitative RT-PCR and Western blotting respectively.


RESULTS
Atrial tachypacing induced significant nerve sprouting and heterogeneous sympathetic hyperinnervation, and the magnitude of nerve sprouting and hyperinnervation was higher in the RAAW than in the LAAW. Atrial beta-NGF mRNA and protein levels were significantly increased at the RAAW and LAAW, and the upregulation of beta-NGF expression was greater at the RAAW than at the LAAW in the control group. The beta-NGF protein level was positively correlated with the density of sympathetic nerves in all groups. Probucol decreased the increase of CRP concentration and attenuated atrial oxidative stress caused by atrial tachypacing. In addition, probucol could effectively inhibit atrial beta-NGF upregulation, significantly attenuate atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and dramatically reduce the inducibility and duration of AF.


CONCLUSIONS
The atrial over-expression of beta-NGF possibly caused by increased oxidative stress and inflammation may be the main mechanism underlying atrial autonomic remodeling during AF. Probucol attenuates atrial autonomic remodeling possibly by its antioxidant and anti-inflammatory actions.
Gong
Yong-tai
YT
Cardiovascular Department, First Clinical Hospital, Harbin Medical University, Heilongjiang, China.
Li
Wei-min
WM
Li
Yue
Y
Yang
Shu-sen
SS
Sheng
Li
L
Yang
Ning
N
Shan
Hong-bo
HB
Xue
Hong-jie
HJ
Liu
Wei
W
Yang
Bao-feng
BF
Dong
De-li
DL
Li
Bao-xin
BX
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000378:metabolism; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006325:Heart Atria; D007150:Immunohistochemistry; D008297:Male; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011341:Probucol / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D002097:C-Reactive Protein; D020932:Nerve Growth Factor; D011341:Probucol; D009638:Norepinephrine