title: Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation.
abstract: OBJECTIVE
  Enhanced oxidative stress is involved in mediating the endothelial dysfunction associated with hypertension. The aim of this study was to investigate the relative contributions of pro-oxidant and anti-oxidant enzymes to the pathogenesis of endothelial dysfunction in genetic hypertension.
  
  
  METHODS
  Dilator responses to endothelium-dependent and endothelium-independent agents such as acetylcholine (ACh) and sodium nitroprusside were measured in the thoracic aortas of 28-week-old spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar Kyoto rats (WKY). The activity and expression (mRNA and protein levels) of endothelial nitric oxide synthase (eNOS), p22-phox, a membrane-bound component of NAD(P)H oxidase, and antioxidant enzymes, namely, superoxide dismutases (CuZn- and Mn-SOD), catalase and glutathione peroxidase (GPx), were also investigated in aortic rings.
  
  
  RESULTS
  Relaxant responses to ACh were attenuated in phenylephrine-precontracted SHR aortic rings, despite a 2-fold increase in eNOS expression and activity. Although the activity and/or expression of SODs, NAD(P)H oxidase (p22-phox) and GPx were elevated in SHR aorta, catalase activity and expression remained unchanged compared to WKY. Pretreatment of SHR aortic rings with the inhibitor of xanthine oxidase, allopurinol, and the inhibitor of cyclooxygenase, indomethacin, significantly potentiated ACh-induced relaxation. Pretreatment of SHR rings with catalase and Tiron, a superoxide anion (O(2)(-)) scavenger, increased the relaxant responses to the levels observed in WKY rings whereas pyrogallol, a O(2)(-)-generator, abolished relaxant responses to ACh.
  
  
  CONCLUSIONS
  These data demonstrate that dysregulation of several enzymes, resulting in oxidative stress, contributes to the pathogenesis of endothelial dysfunction in SHR and indicate that the antioxidant enzyme catalase is of particular importance in the reversal of this defect.
authors.affiliation: Department of Medicine, Institute of Clinical Science, Block B, Queen's University Belfast, Grosvenor Road, Belfast, Northern Ireland BT12 6BJ, UK.
authors.forename: Sibel
authors.initials: S
authors.lastname: Ulker
authors.forename: Dorothy
authors.initials: D
authors.lastname: McMaster
authors.forename: Pascal P
authors.initials: PP
authors.lastname: McKeown
authors.forename: Ulvi
authors.initials: U
authors.lastname: Bayraktutan
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001013:Aorta, Thoracic; D002374:Catalase / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D026901:Membrane Transport Proteins; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D026901:Membrane Transport Proteins; D020030:Nitric Oxide Donors; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D002374:Catalase; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D000109:Acetylcholine