title: Antioxidants condition pleiotropic vascular responses to exogenous H(2)O(2): role of modulation of vascular TP receptors and the heme oxygenase system.
abstract: OBJECTIVE
  Hydrogen peroxide (H(2)O(2)), a nonradical oxidant, is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported, we examined the hypothesis that the ability of H(2)O(2) to effect vasoconstriction or dilation is conditioned by redox mechanisms and may be modulated by antioxidants.
  
  
  RESULTS
  Exogenous H(2)O(2) (0.1-10.0 μM), dose-dependently reduced the internal diameter of rat renal interlobular and 3rd-order mesenteric arteries (p<0.05). This response was obliterated in arteries pretreated with antioxidants, including tempol, pegylated superoxide dismutase (PEG-SOD), butylated hydroxytoluene (BHT), and biliverdin (BV). However, as opposed to tempol or PEG-SOD, BHT & BV, antioxidants targeting radicals downstream of H(2)O(2), also uncovered vasodilation.
  
  
  RESULTS
  Redox-dependent vasoconstriction to H(2)O(2) was blocked by inhibitors of cyclooxygenase (COX) (indomethacin-10 μM), thromboxane (TP) synthase (CGS13080-10 μM), and TP receptor antagonist (SQ29548-1 μM). However, H(2)O(2) did not increase vascular thromboxane B(2) release; instead, it sensitized the vasculature to a TP agonist, U46619, an effect reversed by PEG-SOD. Antioxidant-conditioned dilatory response to H(2)O(2) was accompanied by enhanced vascular heme oxygenase (HO)-dependent carbon monoxide generation and was abolished by HO inhibitors or by HO-1 & 2 antisense oligodeoxynucleotides treatment of SD rats.
  
  
  CONCLUSIONS
  These results demonstrate that H(2)O(2) has antioxidant-modifiable pleiotropic vascular effects, where constriction and dilation are brought about in the same vascular segment. H(2)O(2)-induced oxidative stress increases vascular TP sensitivity and predisposes these arterial segments to constrictor prostanoids. Conversely, vasodilation is reliant upon HO-derived products whose synthesis is stimulated only in the presence of antioxidants targeting radicals downstream of H(2)O(2).
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA. nitin.puri@utoledo.edu
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Sumit R
authors.initials: SR
authors.lastname: Monu
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lamon
authors.forename: Yilun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.forename: Alberto
authors.initials: A
authors.lastname: Nasjletti
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D001808:Blood Vessels / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000975:Antioxidants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D011725:Pyridines; D017482:Receptors, Thromboxane; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C037787:pirmagrel; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing)