title: Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension.
abstract: OBJECTIVE
  The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension.
  
  
  METHODS
  To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha)), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O(2)) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day).
  
  
  RESULTS
  Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF(1alpha) plasma levels rose from 8.2+/-0.8 to 12.2+/-2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF(1alpha) levels (each P<0.05 vs. hypoxia).
  
  
  CONCLUSIONS
  Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.
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: Cornelia
authors.initials: C
authors.lastname: Lorenz
authors.forename: Konrad
authors.initials: K
authors.lastname: Wolf
authors.forename: Peter
authors.initials: P
authors.lastname: Sandner
authors.forename: Günter A J
authors.initials: GA
authors.lastname: Riegger
authors.forename: Michael
authors.initials: M
authors.lastname: Pfeifer
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D002908:Chronic Disease; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000860:Hypoxia; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008297:Male; D023421:Models, Animal; D008981:Molsidomine / Q000627:therapeutic use*; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D010666:Phenylpropionates / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D013599:Systole; D017725:Ventricular Pressure
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D020030:Nitric Oxide Donors; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C107831:darusentan; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D008981:Molsidomine; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase