A Novel model of dexamethasone-induced hypertension: Use in investigating the role of tyrosine hydroxylase

Alexandra E. Soto-Piña, Cynthia Franklin, C. S.Sheela Rani, Helmut Gottlieb, Carmen Hinojosa-Laborde, Randy Strong

Research output: Contribution to journalArticle

6 Scopus citations

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, a-methyl-paratyrosine (a-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative realtime 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 115.0 6 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 adrenalmedulla, and a-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine40) 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.

Original languageEnglish (US)
Pages (from-to)528-536
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume358
Issue number3
DOIs
StatePublished - Sep 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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