BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension 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.
Bonvallet
S T
ST
Division of Pulmonary Sciences and Critical Care, University of Colorado Health Sciences Center, Denver 80262.
Zamora
M R
MR
Hasunuma
K
K
Sato
K
K
Hanasato
N
N
Anderson
D
D
Sato
K
K
Stelzner
T J
TJ
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)