Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation.
BACKGROUND
Reoxygenation of hypoxic myocardium during repair of congenital heart defects results in poor ventricular function and cellular injury. Endothelin-1 (ET-1), a potent vasoconstrictor that increases during hypoxia, may suppress myocardial function and activate leukocytes. The objective was to determine whether administration of an endothelin receptor antagonist could improve ventricular function and decrease cardiac injury after hypoxia and reoxygenation.


METHODS
Fourteen piglets underwent 90 minutes of ventilator hypoxia, 1 hour of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery (controls). Nine additional animals received an infusion of Bosentan, an ET(A/B) receptor antagonist, (5 mg/kg per hour) during hypoxia and reoxygenation.


RESULTS
Right and left ventricular dP/dt in controls decreased to 78% and 52% of baseline, respectively, after recovery (p < 0.05). In contrast, Bosentan-treated animals had complete preservation of RV dP/dt and less depression of LV dP/dt. Bosentan reduced the hypoxia and reoxygenation-induced elevation of ET-1 and iNOS mRNA at the end of recovery (p < 0.05). Bosentan-treated animals had diminished myocardial myeloperoxidase activity and lipid peroxidation compared with controls (p < 0.05). Myocardial apoptotic index, elevated by hypoxia and reoxygenation, was lower in the Bosentan-treated animals (p < 0.05).


CONCLUSIONS
Endothelin-1 receptor antagonism improved functional recovery and decreased leukocyte-mediated injury after reoxygenation. The reduction in cardiac cell death might also improve long-term outcome after reoxygenation injury.
Pearl
J M
JM
Division of Pediatric Cardiothoracic Surgery, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. pearj0@chmcc.org
Nelson
D P
DP
Wagner
C J
CJ
Lombardi
J P
JP
Duffy
J Y
JY
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007262:Infusions, Intravenous; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017466:Receptors, Endothelin / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D018754:Ventricular Dysfunction / Q000473:pathology / Q000503:physiopathology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013449:Sulfonamides; D019001:Nitric Oxide Synthase; D000077300:Bosentan