title: Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice.
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 ± 1.5 vs. 47.8 ± 3.7%, p<0.01, n = 6/group), reduced fasting glucose levels (292 ± 31.8 vs. 511 ± 19.3 mg/dL, p<0.001) and fasting triglycerides (43.3 ± 21 vs. 129.7 ± 29 mg/dL, p<0.05) as compared to DMSO, however body weight was not significantly reduced. Circulating tumor necrosis factor-α and interleukin-1β were reduced after treatment compared to control (257 ± 16.51 vs. 402.3 ± 17.26 and 150.8 ± 12.55 vs. 264 ± 31.85 pg/mL, respectively; P<0.001) Isolated cardiomyocytes from TAD-treated mice showed reduced apoptosis and necrosis.
  
  
  CONCLUSIONS
  We have provided the first evidence that TAD therapy ameliorates circulating inflammatory cytokines and chemokines in a diabetic animal model while improving fasting glucose levels and reducing infarct size following ischemia-reperfusion injury in the heart.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Varma
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: David E
authors.initials: DE
authors.lastname: Durrant
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology* / Q000627:therapeutic use; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D005215:Fasting; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D054411:Receptors, Leptin / Q000235:genetics; D000068581:Tadalafil; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001786:Blood Glucose; D002243:Carbolines; D053583:Interleukin-1beta; D010726:Phosphodiesterase Inhibitors; D054411:Receptors, Leptin; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C515447:leptin receptor, mouse; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5