Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation.
BACKGROUND
Basic studies have suggested that cross-talk exists between the endothelin-A receptor (ET-AR) and tumor necrosis factor signaling pathway. This study tested the hypothesis that administration of an ET-AR antagonist at the separation from cardiopulmonary bypass would alter the tumor necrosis factor activation in the early postoperative period.


METHODS
Patients (n = 44) were randomly allocated to receive bolus infusion of vehicle, 0.1, 0.5, 1, or 2 mg/kg of the ET-AR antagonist (sitaxsentan), at the separation from cardiopulmonary bypass (n = 9, 9, 9, 9, and 8, respectively). Plasma levels of tumor necrosis factor-alpha and soluble tumor necrosis factor receptor 1 and 2 were measured.


RESULTS
Compared with the vehicle group at 24 hours, plasma levels of tumor necrosis factor-alpha and tumor necrosis factor receptor 2 (indicative of receptor activation) were reduced in the 1 mg/kg ET-AR antagonist group (by approximately 13 pg/mL and approximately 0.5 ng/mL, respectively; p < 0.05). Plasma tumor necrosis factor receptor I levels also decreased (by approximately 1 ng/mL) after infusion of the higher doses of the ET-AR antagonist and remained lower (by approximately 3 ng/mL) at 24 hours after infusion (p < 0.05). In addition, a dose effect was observed between the ET-AR antagonist and these indices of tumor necrosis factor activation (p < 0.01).


CONCLUSIONS
This study demonstrated a mechanistic relationship between the ET-AR and tumor necrosis factor receptor activation in the post-cardiac surgery period. Thus, in addition to the potential cardiovascular effects, a selective ET-AR antagonist can modify other biological processes relevant to the post-cardiac surgery setting.
Ford
Rachael L
RL
Division of Cardiothoracic Surgery and Anesthesia, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29403, USA.
Mains
Ira M
IM
Hilton
Ebony J
EJ
Reeves
Scott T
ST
Stroud
Robert E
RE
Crawford
Fred A
FA
Ikonomidis
John S
JS
Spinale
Francis G
FG
D002315:Cardiopulmonary Bypass; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000097:blood; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
D016207:Cytokines; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D007555:Isoxazoles; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C106276:sitaxsentan