Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice

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 (23.261.5 vs. 47.863.7%, p,0.01, n = 6/ group), reduced fasting glucose levels (292631.8 vs. 511619.3 mg/dL, p,0.001) and fasting triglycerides (43.3621 vs