title: Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase.
abstract: BACKGROUND
  Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect.
  
  
  RESULTS
  Short-term treatment with the antioxidants vitamin C (10 micromol/L) or deferoxamine (500 micromol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dt(min)) by -6.8+/-1.7 ms in the presence of vitamin C and by -8.9+/-2.2 ms in the presence of deferoxamine compared with -0.8+/-2.2 ms in the absence of antioxidants (P<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 micromol/L), but not with tetrahydrobiopterin or L-arginine. Protein expression of the NADPH oxidase subunits gp91-phox and p67-phox and myocardial NADPH oxidase activity were significantly increased (P<0.05) in the banded group compared with shams.
  
  
  CONCLUSIONS
  An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.
authors.affiliation: Department of Cardiology, Guy's King's and St Thomas' Schools of Medicine and Biomedical Sciences, King's College London, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: MacCarthy
authors.forename: D J
authors.initials: DJ
authors.lastname: Grieve
authors.forename: J M
authors.initials: JM
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Dunster
authors.forename: F J
authors.initials: FJ
authors.lastname: Kelly
authors.forename: A M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D001708:Biopterins; D013373:Substance P; D008315:Malondialdehyde; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D001120:Arginine; D019255:NADPH Oxidases; C003402:sapropterin; D005978:Glutathione; D003676:Deferoxamine; D001205:Ascorbic Acid