title: Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs.
abstract: We tested the hypothesis that pulmonary endothelial nitric oxide synthase (eNOS) gene expression is primarily regulated by hemodynamic factors and is thus increased in rats with chronic hypoxic pulmonary hypertension. Furthermore, we examined the role of endothelin (ET)-1 in this regulatory process, since ET-1 is able to induce eNOS via activation of the ET-B receptor. Therefore, chronic hypoxic rats (10% O(2)) were treated with the selective ET-A receptor antagonist LU-135252 (50 mg x kg(-1) x day(-1)). Right ventricular systolic pressure and cross-sectional medial vascular wall area of pulmonary arteries rose significantly, and eNOS mRNA levels increased 1.8- and 2.6-fold after 2 and 4 wk of hypoxia, respectively (each P < 0.05). Pulmonary ET-1 mRNA and ET-1 plasma levels increased significantly after 4 wk of hypoxia (each P < 0.05). LU-135252 reduced right ventricular systolic pressure, vascular remodeling, and eNOS gene expression in chronic hypoxic rats (each P < 0.05), whereas ET-1 production was not altered. We conclude that eNOS expression in chronic hypoxic rat lungs is modified predominantly by hemodynamic factors, whereas the ET-B receptor-mediated pathway and hypoxia seem to be less important.
authors.affiliation: Department of Internal Medicine II, University of Regensburg, Germany. friedrich.blumberg@klinik.uni-regensburg.de
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Blumberg
authors.forename: Konrad
authors.initials: K
authors.lastname: Wolf
authors.forename: Michael
authors.initials: M
authors.lastname: Arzt
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lorenz
authors.forename: Günter A J
authors.initials: GA
authors.lastname: Riegger
authors.forename: Michael
authors.initials: M
authors.lastname: Pfeifer
mesh_terms: D000818:Animals; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006400:Hematocrit; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000378:metabolism* / Q000502:physiology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010666:Phenylpropionates / Q000494:pharmacology*; D011312:Pressure; D011651:Pulmonary Artery / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D013599:Systole; D016278:Ventricular Function, Right
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C107831:darusentan; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases