title: NADPH oxidase-derived superoxide augments endothelin-1-induced venoconstriction in mineralocorticoid hypertension.
abstract: Deoxycorticosterone acetate (DOCA)-salt hypertension is characterized by low renin/angiotensin but increased arterial superoxide levels. We have recently reported that the arterial endothelin-1 (ET-1) level is increased, resulting in NADPH oxidase activation and superoxide generation. However, the effect of ET-1 on venous superoxide production and its relation to venoconstriction are unknown. The present study tested the hypotheses that ET-1 stimulates venous NADPH oxidase and superoxide via its ET(A) receptors, resulting in enhanced venoconstriction in DOCA-salt hypertensive rats. Treatment with ET-1 (0.01 to 1 nmol/L), but not the selective ET(B) receptor agonist sarafotoxin s6c, of vena cavas of normal rats concentration-dependently increased superoxide levels, an effect that was abolished by the selective ET(A) receptor antagonist ABT-627. Although the ET-1 level was not increased in the vena cava and plasma, both venous NADPH oxidase activity and superoxide levels were significantly higher in DOCA-salt compared with sham rats. Moreover, ET-1 treatment (10(-9) mol/L, 10 minutes) of isolated vena cavas further elevated superoxide levels in DOCA-salt rats only but not sham rats, an effect that was abrogated by the superoxide scavenger tempol. Similarly, ET-1-induced contractions of isolated vena cavas of DOCA-salt but not sham rats were significantly inhibited by tempol. The NADPH oxidase inhibitor apocynin significantly reduced superoxide levels in vena cavas of DOCA-salt rats and in ET-1-treated vena cavas of normal rats. Finally, in vivo ET(A) receptor blockade by ABT-627 significantly lowered venous superoxide levels and blood pressure in DOCA-salt but not sham rats. These results suggest that superoxide contributes to ET-1-induced venoconstriction through an elevated venous NADPH oxidase activity in mineralocorticoid hypertension.
authors.affiliation: Department of Pharmacology and Toxicology and the Neuroscience Program, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Li
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
authors.forename: Amy K
authors.initials: AK
authors.lastname: Banes
authors.forename: James J
authors.initials: JJ
authors.lastname: Galligan
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Fink
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000077868:Atrasentan; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014684:Venae Cavae / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014757:Viper Venoms / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000098:Acetophenones; D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D018161:Receptors, Mineralocorticoid; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D013481:Superoxides; D003900:Desoxycorticosterone; D000493:Allopurinol; C056165:acetovanillone; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D019331:NG-Nitroarginine Methyl Ester; D000077868:Atrasentan