Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats.
Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ET(A)) receptor causes vasoconstriction, stimulation of ET type B (ET(B)) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ET(B) receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ET(B) receptor deficiency (transgenic sl/sl). After 3 wk of severe hypoxia, the transgenic sl/sl pulmonary vasculature lacked expression of mRNA for the ET(B) receptor and developed exaggerated pulmonary hypertension that was characterized by elevated pulmonary arterial pressure, diminished cardiac output, and increased total pulmonary resistance. Plasma ET-1 was fivefold higher in transgenic sl/sl rats than in transgenic controls. Although mRNA for prepro-ET-1 was not different, mRNA for ET-converting enzyme-1 was higher in transgenic sl/sl than in transgenic control lungs. Hypertensive lungs of sl/sl rats also produced less nitric oxide metabolites and 6-ketoprostaglandin F(1alpha), a metabolite of prostacyclin, than transgenic controls. These findings suggest that the ET(B) receptor plays a protective role in the pulmonary hypertensive response to chronic hypoxia.
Ivy
D Dunbar
DD
Section of Pediatric Cardiology, Pediatric Heart Lung Center, University of Colorado School of Medicine, 1056 E. 19th Ave., Denver, CO 80218, USA. dunbar.ivy@UCHSC.edu
Yanagisawa
Masashi
M
Gariepy
Cheryl E
CE
Gebb
Sarah A
SA
Colvin
Kelley L
KL
McMurtry
Ivan F
IF
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D030801:Animals, Genetically Modified; D015152:Blotting, Northern; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D019332:Endothelin-1 / Q000097:blood; D016232:Endothelins / Q000235:genetics; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D017403:In Situ Hybridization; D019746:Intramolecular Oxidoreductases / Q000032:analysis; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D011498:Protein Precursors / Q000235:genetics; D011652:Pulmonary Circulation / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase