title: Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology.
abstract: OBJECTIVE
  Heart failure is a common antecedent to atrial fibrillation; both heart failure and atrial fibrillation are associated with increased myocardial oxidative stress. Chronic canine heart failure reduces atrial action potential duration and atrial refractoriness. We hypothesized that inducible nitric oxide synthase 2 (NOS2) contributes to atrial oxidative stress and electrophysiologic alterations.
  
  
  RESULTS
  A 16-week canine tachypacing model of heart failure was used (n= 21). At 10 weeks, dogs were randomized to either placebo (n = 12) or active treatment (n = 9) with NOS cofactor, tetrahydrobiopterin (BH(4), 50 mg), and NOS substrate (L-arginine, 3 g) twice daily for 6 weeks. A group of matched controls (n = 7) was used for comparison. Heart failure increased atrial NOS2 and reduced atrial BH(4), while L-arginine was unchanged. Treatment reduced inducible atrial fibrillation and normalized the heart failure-induced shortening of the left atrial myocyte action potential duration. Treatment increased atrial [BH(4)] while [L-arginine] was unchanged. Treatment did not improve left ventricular function or dimensions. Heart failure-induced reductions in atrial [BH(4)] resulted in NOS uncoupling, as measured by NO and superoxide anion (O(2)(·-)) production, while BH(4) and L-arginine treatment normalized NO and O(2)(·-). Heart failure resulted in left atrial oxidative stress, which was attenuated by BH(4) and L-arginine treatment.
  
  
  CONCLUSIONS
  Chronic non-ischaemic heart failure results in atrial oxidative stress and electrophysiologic abnormalities by depletion of BH(4) and uncoupling of NOS2. Modulation of NOS2 activity by repletion of BH(4) may be a safe and effective approach to reduce the frequency of atrial arrhythmias during heart failure.
authors: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA.
authors: Yoshinori
authors: Y
authors: Nishijima
authors: Arun
authors: A
authors: Sridhar
authors: Ingrid
authors: I
authors: Bonilla
authors: Murugesan
authors: M
authors: Velayutham
authors: Mahmood
authors: M
authors: Khan
authors: Radmila
authors: R
authors: Terentyeva
authors: Chun
authors: C
authors: Li
authors: Periannan
authors: P
authors: Kuppusamy
authors: Terry S
authors: TS
authors: Elton
authors: Dmitry
authors: D
authors: Terentyev
authors: Sandor
authors: S
authors: Györke
authors: Jay L
authors: JL
authors: Zweier
authors: Arturo J
authors: AJ
authors: Cardounel
authors: Cynthia A
authors: CA
authors: Carnes
mesh_terms: D000200:Action Potentials; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000378:metabolism; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D016279:Atrial Function, Left / Q000187:drug effects; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000172:deficiency; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006325:Heart Atria / Q000201:enzymology / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D016277:Ventricular Function, Left
chemical_list: D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C003402:sapropterin