Reactive oxygen species are involved in regulating hypocontractility of mesenteric artery to norepinephrine in cirrhotic rats with portal hypertension.
BACKGROUND
Oxidative stress is involved in the hypocontractility of visceral artery to vasoconstrictors and formation of hyperdynamic circulation in cirrhosis with portal hypertension. In the present study, we investigated the effect of reactive oxygen species (ROS) on the mesenteric artery contractility in CCl4-induced cirrhotic rats, and the roles of G protein-coupled receptors (GPCRs) desensitization and RhoA/Rho associated coiled-coil forming protein kinase (ROCK) pathways.


METHODS
The mesenteric artery contraction to norepinephrine (NE) was determined by vessel perfusion system following treatments with apocynin, tempol or PEG-catalase. The protein expression of α1 adrenergic receptor, β-arrestin-2, ROCK-1, moesin and p-moesin was measured by western blot. The interaction between α1 adrenergic receptor and β-arrestin-2 was assessed by co-immunoprecipitation.


RESULTS
Pretreatment with apocynin or PEG-catalase in cirrhotic rats, the hydrogen peroxide level in the mesenteric arteriole was significantly decreased, and the dose-response curve of mesenteric arteriole to NE moved to the left with EC50 decreased. There was no significant change for the expression of α1 adrenergic receptor. However, the protein expression of β-arrestin-2 and its affinity with α1 adrenergic receptor were significantly decreased. The ROCK-1 activity and anti- Y-27632 inhibition in cirrhotic rats increased significantly with the protein expression unchanged. Such effects were not observed in tempol-treated group.


CONCLUSIONS
The H2O2 decrease in mesenteric artery from rats with cirrhosis resulted in down regulation of the β-arrestin-2 expression and its binding ability with α1 adrenergic receptor, thereby affecting the agonist-induced ROCK activation and improving the contractile response in blood vessels.
Department of Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Wei
W
Chen
Department of Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
De-Jun
DJ
Liu
Department of Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Yan-Miao
YM
Huo
Department of Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Zhi-Yong
ZY
Wu
Department of Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Yong-Wei
YW
Sun
D000577:Amides; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006975:Hypertension, Portal / Q000378:metabolism / Q000503:physiopathology; D008103:Liver Cirrhosis; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology*; D018384:Oxidative Stress; D011725:Pyridines; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000577:Amides; C000605257:Arrb2 protein, rat; D019390:Arrestins; D011725:Pyridines; D017382:Reactive Oxygen Species; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C108830:Y 27632; D006861:Hydrogen Peroxide; C578418:ROCK1 protein, rat; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D009638:Norepinephrine
Reactive oxygen species; hypocontractility; mesenteric artery; norepinephrine; portal hypertension.