title: Endothelin-1-induced contraction in veins is independent of hydrogen peroxide.
abstract: Reactive oxygen species (ROS), such as superoxide and H(2)O(2), are capable of modifying vascular tone, although the response to ROS can vary qualitatively among vascular beds, experimental procedures, and species. Endothelin-1 (ET-1) induces superoxide production, which can be dismutated to H(2)O(2). The RhoA/Rho kinase pathway partially mediates ET-1-induced contraction and recently was implicated in superoxide-induced contraction. We hypothesized that H(2)O(2), not superoxide, mediates venous ET-1-induced contraction. Rat thoracic aorta and vena cava contracted to exogenously added H(2)O(2) (1 microM-1 mM) [maximum aortic contraction = 10 +/- 3% of phenylephrine (10 microM) contraction; maximum venous contraction = 85 +/- 13% of norepinephrine (10 microM) contraction]. (+)-(R)-trans-4-(1-aminoethyl-N-4-pyridil)cyclohexanecarboxamide dihydrochloride (Y-27632, 10 microM), a Rho kinase inhibitor, significantly reduced venous H(2)O(2)-induced contraction (15 +/- 1% of control maximum) and reduced maximum ET-1-induced contraction by 59 +/- 1%. However, neither the H(2)O(2) scavenger catalase (100 and 2,000 U/ml) nor cell permeable polyethylene glycol-catalase (163 and 326 U/ml) reduced ET-1-induced contraction in the vena cava. The catalase inhibitor 3-aminotriazole (3-AT) also had no effect on maximal venous ET-1-induced contraction. Basal H(2)O(2) levels were three times higher in the vena cava than in the aorta (vena cava, 0.74 +/- 0.09 nmol H(2)O(2)/mg protein; aorta, 0.24 +/- 0.05 nmol H(2)O(2)/mg protein). ET-1 (100 nM) increased H(2)O(2) in the vena cava but not in the aorta (vena cava, 154.10 +/- 17.29% of control H(2)O(2); aorta, 83.72 +/- 20.20%). Antagonism of either ET(A) or ET(B) receptors with the use of atrasentan (30 nM) or BQ-788 (100 nM), respectively, reduced ET-1 (100 nM)-induced increases in venous H(2)O(2). In summary, ET-1 increased H(2)O(2) in veins but not arteries, and venous ET-1-induced H(2)O(2) production was independent of the contractile properties of ET-1.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, E. Lansing, MI 48824-1317, USA. thakalik@msu.edu
authors.forename: Keshari
authors.initials: K
authors.lastname: Thakali
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Demel
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Fink
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014682:Vena Cava, Inferior / Q000187:drug effects* / Q000502:physiology*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D047908:Intracellular Signaling Peptides and Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; D020742:rhoA GTP-Binding Protein