title: Effects of peroxisome proliferator-activated receptor-β activation in endothelin-dependent hypertension.
abstract: OBJECTIVE
  We analysed the chronic effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonist GW0742 on the renin-independent hypertension induced by deoxycorticosterone acetate (DOCA)-salt.
  
  
  RESULTS
  Rats were treated for 5 weeks with: control-vehicle, control-GW0742 (5 or 20 mg kg(-1) day(-1)), DOCA-vehicle, DOCA-GW0742 (5 or 20 mg kg(-1) day(-1)), DOCA-GSK0660 (1 mg kg(-1) day(-1)), and DOCA-GSK0660-GW0742. Rats receiving DOCA-vehicle showed increased systolic blood pressure, left ventricular and kidney weight indices, endothelin-1 (ET-1), and malondialdehyde plasma levels, urinary iso-PGF2α excretion, impaired endothelium-dependent relaxation to acetylcholine, and contraction to ET-1 when compared with controls. Aortic reactive oxygen species content, NADPH oxidase activity, and p47(phox), p22(phox), NOX-4, glutathione peroxidase 1, hemeoxygenase-1, and preproET-1 expression were increased, whereas catalase and regulators of G protein-coupled signalling proteins (RGS)5 expression were decreased in the DOCA-vehicle group. GW0742 prevented the development of hypertension in a dose-dependent manner but the reduction of renal and cardiac hypertrophy, systemic and vascular oxidative stress markers, and improvement of endothelial dysfunction were only observed after the higher dose. GW0742, at 20 mg kg(-1) day(-1), attenuated ET-1 contraction by increasing RGS5 expression and restored the intracellular redox balance by reducing NADPH-oxidase activity, and by increasing the antioxidant genes expression. The PPAR-β antagonist GSK0660 prevented all vascular changes induced by GW0742 but not its antihypertensive effects.
  
  
  CONCLUSIONS
  Vascular protective effects of GW0742 operate via PPAR-β by interference with the ET-1 signalling as a result of increased expression of RGS5 and up-regulation of antioxidant genes and via PPAR-β-independent mechanisms to decrease blood pressure.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Zarzuelo
authors.forename: Manuel
authors.initials: M
authors.lastname: Gómez-Guzmán
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
authors.forename: Ana María
authors.initials: AM
authors.lastname: Quintela
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D064791:Desoxycorticosterone Acetate; D019332:Endothelin-1 / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D019255:NADPH Oxidases / Q000378:metabolism; D048068:PPAR-beta / Q000502:physiology*; D020710:RGS Proteins / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D064791:Desoxycorticosterone Acetate; D019332:Endothelin-1; D019255:NADPH Oxidases; D048068:PPAR-beta; D020710:RGS Proteins; D017382:Reactive Oxygen Species; D013844:Thiazoles; C491348:Rgs5 protein, rat; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: DOCA-salt hypertension; Endothelial dysfunction; Endothelin-1; PPARβ/δ; Regulators of G protein-coupled signalling proteins