Affiliation:
1. Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
Abstract
Background
The efficacy of P2Y
12
inhibition for the prevention of cardiovascular events in patients with peripheral arterial disease (
PAD
) has been established. However, the therapeutic effects on ischemic limb complications are less clear. Accordingly, we aimed to develop a novel murine model of thrombotic hindlimb ischemia to reflect that found in patients with
PAD
exhibiting ischemic limb symptoms. We further investigated the effects of P2Y
12
deficiency and P2Y
12
inhibition by prasugrel in this model.
Methods and Results
Thrombus formation induced by application of ferric chloride to the femoral artery resulted in a significant reduction in blood flow in the injured limb. In gait analysis using the CatWalk system, moderate difficulties in grounding and weight bearing of the ischemic limb, including reduction of maximum contact area and stance phase duration and increasing in swing phase duration in the ischemic limb, were observed in this model. Blood flow reduction and gait abnormalities gradually recovered over 21 days to levels present before arterial injury. Compared to wild‐type (
WT
) mice, significant increases in blood flow and improvement in gait were observed in P2Y
12
‐deficient mice. In addition, daily oral administration of prasugrel (3 mg/kg per day) to
WT
mice resulted in significant inhibition of blood flow reduction and gait abnormalities to levels found in P2Y
12
deficient mice.
Conclusions
Acute femoral artery thrombosis resulted in hindlimb ischemia and moderate gait abnormalities in mice. In addition, the present study suggests a possible role of P2Y
12
in the complications with thrombotic limb ischemia.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献