title: Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension.
abstract: Adequate production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) requires eNOS coupling promoted by tetrahydrobiopterin (BH(4)). Under pathological conditions such as hypertension, BH(4) is diminished, avoiding eNOS coupling. When eNOS is "uncoupled", it yields a superoxide anion instead of NO. Peroxisome proliferator activated receptors (NR1C) are a family of nuclear receptors activated by ligand. Clofibrate, a member of a hypolipidemic class of drugs, acts by activating the alpha isoform of NR1C. To determine the participation of NR1C1 activation in BH(4) and dihydrobiopterin (BH(2)) metabolism and its implications on eNOS coupling in hypertension, we performed aortic coarctation (AoCo) at inter-renal level on male Wistar rats in order to have a hypertensive model. Rats were divided into the following groups: Sham+vehicle (Sham-V); AoCo+vehicle (AoCo-V); Sham+clofibrate (Sham-C), and AoCo+clofibrate (AoCo-C). Clofibrate (7 days) increased eNOS coupling in the AoCo-C group compared with AoCo-V. Clofibrate also recovered the BH(4):BH(2) ratio in control values and prevented the rise in superoxide anion production, lipoperoxidation, and reactive oxygen species production. In addition, clofibrate increased GTP cyclohydrolase-1 (GTPCH-1) protein expression, which is related with BH(4) recovered production. NR1C1 stimulation re-establishes eNOS coupling, apparently through recovering the BH(4):BH(2) equilibrium and diminishing oxidative stress. Both can contribute to high blood pressure attenuation in hypertension secondary to AoCo.
authors.affiliation: Department of Pharmacology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, 14080 México, DF, Mexico.
authors.forename: Luz Graciela
authors.initials: LG
authors.lastname: Cervantes-Pérez
authors.forename: María de la Luz
authors.initials: Mde L
authors.lastname: Ibarra-Lara
authors.forename: Bruno
authors.initials: B
authors.lastname: Escalante
authors.forename: Leonardo
authors.initials: L
authors.lastname: Del Valle-Mondragón
authors.forename: Hilda
authors.initials: H
authors.lastname: Vargas-Robles
authors.forename: Francisca
authors.initials: F
authors.lastname: Pérez-Severiano
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pastelín
authors.forename: María Alicia
authors.initials: MA
authors.lastname: Sánchez-Mendoza
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology*; D004195:Disease Models, Animal; D006136:GTP Cyclohydrolase / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C017226:7,8-dihydrobiopterin; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; C003402:sapropterin; D002994:Clofibrate