Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension

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• 作者：Blumberg ; Friedrich C. ; Lorenz ; Cornelia ; Wolf ; Konrad ; Sandner ; Peter ; Riegger ; Gü ; nter A.J. ; et. al.
• 关键词：Endothelial factors ; Endothelins ; Hypoxia/anoxia ; Prostaglandins ; Pulmonary circulation
• 刊名：Cardiovascular Research
• 出版年：2002
• 出版时间：July, 2002
• 年：2002
• 卷：55
• 期：1
• 页码：171-177
• 全文大小：339 K

文摘

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_1α (6-keto-PGF_1α), 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-PGF_1α 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_1α 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.