title: N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats.
abstract: BACKGROUND
  Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes.
  
  
  RESULTS
  Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes.
  
  
  CONCLUSIONS
  NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.forename: Shigang
authors.initials: S
authors.lastname: Qiao
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Lei
authors.forename: Yanan
authors.initials: Y
authors.lastname: Liu
authors.forename: Kwok F J
authors.initials: KF
authors.lastname: Ng
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Michael G
authors.initials: MG
authors.lastname: Irwin
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D052242:Adiponectin / Q000096:biosynthesis / Q000378:metabolism*; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D052279:Creatine Kinase, MB Form / Q000097:blood; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015237:Dinoprost / Q000031:analogs & derivatives; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood; D028421:Isoprostanes / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D052242:Adiponectin; D000975:Antioxidants; D015415:Biomarkers; D001786:Blood Glucose; D015850:Interleukin-6; D028421:Isoprostanes; D054419:Receptors, Adiponectin; D014409:Tumor Necrosis Factor-alpha; C075750:8-epi-prostaglandin F2alpha; D000493:Allopurinol; D015237:Dinoprost; D052279:Creatine Kinase, MB Form; D000111:Acetylcysteine