The ETA-Receptor Antagonist LU 135252 Prevents the Progression of Established Pulmonary Hypertension Induced by Monocrotaline in Rats

To investigate the role of endothelin-1 (ET-1) in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a recently described endothelin-receptor antagonist (ETA), BQ123, on the development of this process. Intraperitoneal osmotic pumps were placed into 8-wk-old Sprague-Dawley rats that received either saline or BQ123 (0.15 mg/h). The rats were maintained in room air normoxia or placed in a hypobaric chamber (380 Torr) for 2 wk to induce hypoxic pulmonary hypertension. There were no hemodynamic differences between normoxic rats treated with either saline or BQ123. However, treatment with BQ123 attenuated the hypoxia-induced increase in pulmonary arterial mean pressure and total pulmonary resistance index by 60 and 87% respectively. There was also a reduction in hypoxia-induced right ventricular hypertrophy in the BQ123 group. Histological studies performed using a barium-gelatin fixation technique in hypoxic BQ123-treated animals demonstrated a decrease in medial wall thickness in arteries corresponding to the respiratory and terminal bronchioles, respectively. Similarly, there was a significant reduction in the degree of muscularization of more distal vessels at the level of alveolar ducts in BQ123-treated hypoxic rats. We conclude that the ETA-receptor antagonist BQ123 attenuates the development of hypoxic pulmonary hypertension in rats in vivo, thereby suggesting a possible contributing role for ET-1 and the ETA receptor in the pathogenesis of this process.

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The orally active nonpeptide selective endothelin ETA receptor antagonist YM598 prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats

European Journal of Pharmacology ◽

10.1016/j.ejphar.2004.06.021 ◽

2004 ◽

Vol 496 (1-3) ◽

pp. 129-139 ◽

Cited By ~ 15

Author(s):

Hironori Yuyama ◽

Akira Fujimori ◽

Masanao Sanagi ◽

Akiko Koakutsu ◽

Katsumi Sudoh ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Receptor Antagonist ◽

Eta Receptor ◽

Eta Receptor Antagonist ◽

Orally Active

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TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

Pediatric Research ◽

10.1203/00006450-200109000-00013 ◽

2001 ◽

Vol 50 (3) ◽

pp. 374-383 ◽

Cited By ~ 33

Author(s):

Thérèse Perreault ◽

John W Berkenbosch ◽

Keith J Barrington ◽

E Radford Decker ◽

Chengde Wu ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Receptor Antagonist ◽

Neonatal Hypoxia ◽

Eta Receptor ◽

Eta Receptor Antagonist

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ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1995.269.5.l690 ◽

1995 ◽

Vol 269 (5) ◽

pp. L690-L697 ◽

Cited By ~ 38

Author(s):

V. S. DiCarlo ◽

S. J. Chen ◽

Q. C. Meng ◽

J. Durand ◽

M. Yano ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Receptor Antagonist ◽

Vascular Remodeling ◽

Ventricular Hypertrophy ◽

Chronic Hypoxia ◽

Right Ventricular Hypertrophy ◽

Pulmonary Vascular Remodeling ◽

Eta Receptor ◽

Eta Receptor Antagonist

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

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