Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension.
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.
Blumberg
Friedrich C
FC
Department of Internal Medicine II, University of Regensburg, Germany. friedrich.blumberg@klinik.uni-regensburg.de
Lorenz
Cornelia
C
Wolf
Konrad
K
Sandner
Peter
P
Riegger
Günter A J
GA
Pfeifer
Michael
M
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
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