title: Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system.
abstract: BACKGROUND
  We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR.
  
  
  METHODS
  IR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT1) were assessed by immunofluorescence.
  
  
  RESULTS
  IR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT1 receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.
  
  
  CONCLUSIONS
  XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. helbassossy@kau.edu.sa.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt. helbassossy@kau.edu.sa.
authors.forename: Hany M
authors.initials: HM
authors.lastname: El-Bassossy
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. m.l.watson@bath.ac.uk.
authors.forename: Malcolm L
authors.initials: ML
authors.lastname: Watson
mesh_terms: D000284:Administration, Oral; D000493:Allopurinol / Q000008:administration & dosage / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D059305:Diet, High-Fat; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000473:pathology*; D007333:Insulin Resistance; D007545:Isoproterenol; D008297:Male; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D014463:Ultrasonography; D014527:Uric Acid / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000804:Angiotensin II; D014527:Uric Acid; D000493:Allopurinol; D014969:Xanthine Oxidase; D007545:Isoproterenol