title: Exogenous ghrelin attenuates the progression of chronic hypoxia-induced pulmonary hypertension in conscious rats.
abstract: Chronic exposure to hypoxia, a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy, and is, therefore, closely associated with heart failure and increased mortality. Ghrelin, originally identified as an endogenous GH secretagogue, has recently been shown to possess potent vasodilator properties, likely involving modulation of the vascular endothelium and its associated vasoactive peptides. In this study we hypothesized that ghrelin would impede the pathogenesis of pulmonary arterial hypertension during chronic hypoxia (CH). PAP was continuously measured using radiotelemetry, in conscious male Sprague Dawley rats, in normoxia and during 2-wk CH (10% O(2)). During this hypoxic period, rats received a daily sc injection of either saline or ghrelin (150 microg/kg). Subsequently, heart and lung samples were collected for morphological, histological, and molecular analyses. CH significantly elevated PAP in saline-treated rats, increased wall thickness of peripheral pulmonary arteries, and, consequently, induced right ventricular hypertrophy. In these rats, CH also led to the overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA within the lung. Exogenous ghrelin administration attenuated the CH-induced overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA. Consequently, ghrelin significantly attenuated the development of pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy. These results demonstrate the therapeutic benefits of ghrelin for impeding the pathogenesis of pulmonary hypertension and right ventricular hypertrophy, particularly in subjects prone to CH (e.g. pulmonary disorders).
authors.affiliation: Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Daryl O
authors.initials: DO
authors.lastname: Schwenke
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hosoda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000465:Algorithms; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D003243:Consciousness; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D054439:Ghrelin / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D019332:Endothelin-1; D005230:Fatty Acids, Nonesterified; D054439:Ghrelin; D012333:RNA, Messenger; D052250:Nitric Oxide Synthase Type III