Role of endothelial nitric oxide synthase and vagal activity in the endothelial protection of atorvastatin in ischemia/reperfusion injury.
Vascular endothelial dysfunction plays a pivotal role in the development and maintenance of ischemia/reperfusion (I/R) injury. Statins, developed as lipid-lowering drugs, partially restore vagal activity and exhibit pleiotropic effects. This study was aimed at determining the effect of atorvastatin (ATV) on endothelial dysfunction in peripheral resistance arteries after I/R injury. After pretreatment with ATV (10 mg·kg·d) or its vehicle for 3 days, the superior mesenteric artery was occluded for 60 minutes and reperfusion for 90 minutes or the rats were anesthetized without being subjected to ischemia. In the ATV-treated I/R group, the increased contractions to KCl and 5-hydroxytryptamine induced by I/R were ameliorated, and attenuated endothelium-dependent relaxations to acetylcholine (ACh) were normalized. The restored relaxation to ACh was abolished by N-nitro-L-arginine methyl ester. ATV prevented the structural damage of vascular endothelial cells. Furthermore, the activities of phosphatidylinositol-3-kinase, Akt, and endothelial nitric oxide synthase were elevated in mesenteric arteries after ATV treatment. In addition, I/R-induced increment of endothelial cells apoptosis was also attenuated by ATV. Intriguingly, ATV also increased baroreflex sensitivity and serum ACh content after I/R. In conclusion, the endothelial protective effect of ATV in peripheral arteries is associated with the activated phosphatidylinositol-3-kinase/Akt/endothelial nitric oxide synthase pathway and restored vagal activity.
Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, PR China.
Xue-Yuan
XY
Bi
Xi
X
He
Ming
M
Zhao
Xiao-Jiang
XJ
Yu
Wei-Jin
WJ
Zang
D000109:Acetylcholine / Q000097:blood / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D014630:Vagus Nerve / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D058539:Phosphatidylinositol 3-Kinase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester