© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension
aDepartment of Internal Medicine II, University of Regensburg, 93042 Regensburg, Germany
bInstitute of Physiology, University of Regensburg, 93042 Regensburg, Germany
friedrich.blumberg{at}klinik.uni-regensburg.de
* Corresponding author. Tel.: +49-941-944-7281; fax: +49-941-9447282
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 F1
(6-keto-PGF1), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O2) 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-PGF1 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-PGF1 levels (each P<0.05 vs. hypoxia). Conclusion: 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.
KEYWORDS Endothelial factors; Endothelins; Hypoxia/anoxia; Prostaglandins; Pulmonary circulation
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