Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction.
Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ET(A) and ET(B) receptors. Although activation of the ET(A) receptor causes vasoconstriction, stimulation of the ET(B) receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ET(B) receptor in the pulmonary circulation, we studied a genetic rat model of ET(B) receptor deficiency [transgenic(sl/sl)]. We hypothesized that deficiency of the ET(B) receptor would predispose the transgenic(sl/sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic(sl/sl) rats are ET(B) deficient because they lack ET(B) mRNA in the pulmonary vasculature, have minimal ET(B) receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic(sl/sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic(sl/sl) rat lung. These findings suggest that the ET(B) receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ET(B) receptor activity can contribute to the pathogenesis of pulmonary hypertension.
Ivy
D
D
Pediatric Heart Lung Center, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80218, USA. dunbar.ivy@uchsc.edu
McMurtry
I F
IF
Yanagisawa
M
M
Gariepy
C E
CE
Le Cras
T D
TD
Gebb
S A
SA
Morris
K G
KG
Wiseman
R C
RC
Abman
S H
SH
D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D000860:Hypoxia / Q000378:metabolism*; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D019332:Endothelin-1; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D004299:Dopamine beta-Hydroxylase