Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function.
BACKGROUND
Acute hypoxia results in increased pulmonary vascular resistance. Despite reoxygenation, pulmonary vascular resistance remains elevated and pulmonary function is altered. Endothelin-1 might contribute to hypoxia-reoxygenation-induced pulmonary hypertension and to reoxygenation injury by stimulating leukocytes. This study was carried out using an established model of hypoxia and reoxygenation to determine whether endothelin-1 blockade with Bosentan could prevent hypoxia-reoxygenation-induced pulmonary hypertension and reoxygenation injury.


METHODS
Twenty neonatal piglets underwent 90 minutes of hypoxia, 60 minutes of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery. Control animals (n = 12) received no drug treatment, whereas the treatment group (n = 8) received the endothelin-1 receptor antagonist, Bosentan, throughout hypoxia.


RESULTS
In controls, pulmonary vascular resistance increased during hypoxia to 491% of baseline and remained elevated after reoxygenation; however in the Bosentan group, it increased to only 160% of baseline by end-hypoxia, then decreased to 76% at end-recovery. Arterial endothelin-1 levels in controls increased to 591% of baseline after reoxygenation. Arterial nitrite levels decreased during hypoxia in controls but were maintained in the Bosentan group. Consequently, animals in the Bosentan group had better postreoxygenation pulmonary vascular resistance, A-a gradient, and airway resistance along with lower myeloperoxidase levels than controls.


CONCLUSIONS
Acute hypoxia and postreoxygenation pulmonary hypertension was attenuated by Bosentan, which maintained nitric oxide levels during hypoxia, decreased leukocyte-mediated injury, and improved pulmonary function.
Pearl
J M
JM
Division of Pediatric Cardiothoracic Surgery, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. pearj0@chmcc.org
Wellmann
S A
SA
McNamara
J L
JL
Lombardi
J P
JP
Wagner
C J
CJ
Raake
J L
JL
Nelson
D P
DP
D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D002315:Cardiopulmonary Bypass; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology; D010100:Oxygen / Q000097:blood*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; D009569:Nitric Oxide; D000077300:Bosentan; D010100:Oxygen