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Original Articles: Adult Cardiac

Endothelin-A Receptor Inhibition After Cardiopulmonary Bypass: Cytokines and Receptor Activation

Division of Cardiothoracic Surgery and Anesthesia, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina

Accepted for publication June 23, 2008.

^_* Address correspondence to Dr Spinale, Cardiothoracic Surgery, Strom Thurmond Research Bldg, 114 Doughty St, Room 625, Medical University of South Carolina, Charleston, SC 29403 (Email: wilburnm{at}musc.edu).

Presented at the Basic Science Forum of the Fifty-fourth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 7–10, 2007.

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- 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- 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.

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