Endothelin-A receptor antagonist prevents acute hypoxia-induced pulmonary hypertension in the rat.
Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin-1 (ET-1) levels and with selective enhancement in ET-1 peptide and mRNA and endothelin-A (ETA) receptor mRNA levels in rat lung. The current study tested the hypothesis that endogenous ET-1 can account for hypoxia-induced pulmonary hypertension via a paracrine effect on ETA receptors in lung. Intravenous infusion of the ETA receptor antagonist BQ-123 (D-Trp-D-Asp-Pro-D-Val-Leu) (0.4 mg/microliters at 1 microliter/h) into Sprague-Dawley rats beginning 4 h before and for 90 min during normobaric hypoxia (10% O2) markedly attenuated the hypoxic response: mean pulmonary artery pressure increased from 17.2 +/- 0.7 to 29.0 +/- 1.2 mmHg in saline control rats but did not increase from baseline in BQ-123-treated rats. BQ-123 did not alter systemic arterial pressure, heart rate, or plasma endothelin-1 levels. These findings suggest that ET-1 synthesized in lung in response to hypoxia acts locally on ETA receptors to cause pulmonary hypertension.
Department of Medicine, University of Alabama at Birmingham 35294.
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S
Oparil
S J
SJ
Chen
Q C
QC
Meng
T S
TS
Elton
M
M
Yano
Y F
YF
Chen
D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)