Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats.
BACKGROUND
Atrial fibrillation (AF) per se causes atrial endocardial dysfunction leading to local coagulation imbalance on the internal surface of the atrium, which contributes to thrombus formation in the fibrillating left atrium.


METHODS
To test a hypothesis that blockade of angiotensin II type 1 receptor (AT1-receptor) prevents the endocardial dysfunction by AF, we examined the effects of olmesartan on the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), endothelial nitric oxide synthase (eNOS) and plasminogen activator inhibitor-1 (PAI-1) in the endocardium of the rapidly paced rat atria.


RESULTS
Rapid pacing induced a significant decrease in TFPI, TM and eNOS and an increase in PAI-1 protein in the left atrium. Pre-administration of low-dose olmesartan significantly prevented the down-regulation of TFPI, TM and eNOS and also attenuated the up-regulation of PAI-1. Immunohistochemistry identified these changes predominantly in the atrial endocardium. While the drug was without any effect on mRNA levels of TFPI, TM and eNOS, there was a significant decrease in its PAI-1 mRNA expression.


CONCLUSIONS
AT1-receptor blocker could partially prevent the atrial endocardial dysfunction by rapid atrial pacing, which would provide one theoretical basis for beneficial effects for stroke prevention in AF.
Yamashita
Takeshi
T
The Cardiovascular Institute, Roppongi 7-3-10, Tokyo 106-0032, Japan. yamt-tky@umin.ac.jp
Sekiguchi
Akiko
A
Kato
Takeshi
T
Tsuneda
Takayuki
T
Iwasaki
Yu-ki
YK
Sagara
Kouichi
K
Iinuma
Hiroyuki
H
Sawada
Hitoshi
H
Aizawa
Tadanori
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001281:Atrial Fibrillation / Q000150:complications* / Q000209:etiology; D002304:Cardiac Pacing, Artificial / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004699:Endocardium / Q000503:physiopathology; D006325:Heart Atria; D006331:Heart Diseases / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013777:Tetrazoles; D018180:Thrombomodulin; C051928:lipoprotein-associated coagulation inhibitor; C437965:olmesartan; D052250:Nitric Oxide Synthase Type III