title: Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus.
abstract: BACKGROUND
  Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (
  
  
  BACKGROUND
  NCT02009527).
  
  
  METHODS
  Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline.
  
  
  RESULTS
  The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions.
  
  
  CONCLUSIONS
  Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.
authors: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Oskar
authors: O
authors: Kövamees
authors: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Alexey
authors: A
authors: Shemyakin
authors: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: John
authors: J
authors: Pernow
mesh_terms: D000368:Aged; D001119:Arginase / Q000037:antagonists & inhibitors*; D003324:Coronary Artery Disease / Q000150:complications*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D017534:Radial Artery / Q000187:drug effects; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D001119:Arginase