原创力文档anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice糖尿病小鼠抗炎和他达拉非心血管效应.pdfVIP
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anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice糖尿病小鼠抗炎和他达拉非心血管效应
Anti-Inflammatory and Cardioprotective Effects of
Tadalafil in Diabetic Mice
Amit Varma, Anindita Das, Nicholas N. Hoke, David E. Durrant, Fadi N. Salloum, Rakesh C. Kukreja*
Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
Abstract
Background: Insulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic
inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce
circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized
that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose
and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice.
Methods: Twenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days.
Body weight and fasting plasma glucose levels were determined weekly. Upon completion, hearts were isolated and
subjected to 30 min global ischemia followed by 60 min reperfusion in a Langendorff model. Plasma samples were taken
for cytokine analysis and fasting triglyceride levels. Infarct size was measured using computer morphometry of tetrazolium
stained sections. Additionally, ventricular cardiomyocytes were isolated and subjected to 40 min of simulated ischemia and
reoxygenation. Necrosis was determined using trypan blue exclusion and LDH release assay and apoptosis was assessed by
TUNEL assay after 1 h or 18 h of reoxygenation, respectively.
Results: Treatment with TAD caused a reduction in infarct size in the diabetic heart (23.2 61.5 vs. 47.863.7%, p,0.01, n = 6/
group), reduced f
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