title: A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase.
abstract: Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, α-methyl-para-tyrosine (α-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative real-time polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by +15.0 ± 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and α-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine(40)) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis.
authors.affiliation: Universidad Autónoma del Estado de México, Facultad de Medicina, Toluca, México (A.E.S.-P.); Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.S.S.R., C.H.-L., R.S.); Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (H.G., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas (R.S.) aesotop@uaemex.mx.
authors.forename: Alexandra E
authors.identifier: 0000-0002-3289-5510
authors.initials: AE
authors.lastname: Soto-Piña
authors.affiliation: Universidad Autónoma del Estado de México, Facultad de Medicina, Toluca, México (A.E.S.-P.); Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.S.S.R., C.H.-L., R.S.); Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (H.G., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas (R.S.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Franklin
authors.affiliation: Universidad Autónoma del Estado de México, Facultad de Medicina, Toluca, México (A.E.S.-P.); Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.S.S.R., C.H.-L., R.S.); Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (H.G., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas (R.S.).
authors.forename: C S Sheela
authors.initials: CS
authors.lastname: Rani
authors.affiliation: Universidad Autónoma del Estado de México, Facultad de Medicina, Toluca, México (A.E.S.-P.); Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.S.S.R., C.H.-L., R.S.); Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (H.G., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas (R.S.).
authors.forename: Helmut
authors.initials: H
authors.lastname: Gottlieb
authors.affiliation: Universidad Autónoma del Estado de México, Facultad de Medicina, Toluca, México (A.E.S.-P.); Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.S.S.R., C.H.-L., R.S.); Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (H.G., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas (R.S.).
authors.forename: Carmen
authors.initials: C
authors.lastname: Hinojosa-Laborde
authors.affiliation: Universidad Autónoma del Estado de México, Facultad de Medicina, Toluca, México (A.E.S.-P.); Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.S.S.R., C.H.-L., R.S.); Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (H.G., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas (R.S.).
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
mesh_terms: D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D012694:Serine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019805:alpha-Methyltyrosine / Q000494:pharmacology
chemical_list: D012694:Serine; D019805:alpha-Methyltyrosine; D003907:Dexamethasone; D014446:Tyrosine 3-Monooxygenase