Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation

Abstract

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.

Figures

Figure 1

The absolute changes in plasma endothelin (panel A), interleukin-6 (panel B), and interleukin-10 (panel C) concentrations were computed at 0.5, 6, and 24 hours following infusion of increasing doses of the endothelin-A receptor (ET-AR) antagonist (0.1–2.0 mg/kg, black bars) or vehicle (0 mg/kg, white bars). At 24 hours post infusion, plasma endothelin levels were increased, except in the high dose ET-AR group. Plasma interleukin-6 levels were increased at 6 hours post infusion in all of the ET-AR antagonist groups. In contrast, interleukin-10 levels were reduced following infusion of the higher doses of the ET-AR antagonist, and this effect persisted at longer time points. (*p

Figure 2

The absolute changes in plasma tumor necrosis factor-α (TNF: panel A), TNF Receptor I (panel B), and TNF Receptor II (panel C) concentrations were computed at 0.5, 6, and 24 hours following infusion of increasing doses of the endothelin-A receptor (ET-AR) antagonist (0.1–2.0 mg/kg, black bars) or vehicle (0 mg/kg, white bars). At 24 hours post infusion, plasma TNF levels were reduced in the higher dose of the ET-AR antagonist when compared to the vehicle group. Plasma TNF Receptor I levels decreased immediately following infusion of the higher doses of the ET-AR antagonist, and this effect persisted at longer time points. Similarly at 24 hours post infusion, plasma TNF Receptor II levels were reduced in the higher doses of the ET-AR antagonist when compared to the vehicle group. (*p

Figure 3

Schematic of the potential interaction of the endothelin-A receptor (ET-AR) and the tumor necrosis factor-α (TNF) pathway. Binding of endothelin (ET) to the ET-AR caused the induction of an intracellular cascade which culminates in both pre-transcriptional and transcriptional events. Specifically, ET-AR can result in the formation of phosphorylation intermediates, which in turn could cause phosphorylation and mobilization of TNF convertase (TACE) to the cell membrane. TACE in turn would cause solubilization of membrane bound TNF and ultimately binding to the TNF receptor complex (TNFR). The binding of TNF to the TNFR will ultimately be proteolytically processed and yield soluble TNFR complexes, which can be quantified in the plasma. Stimulation of both the ET-AR and TNFR will cause binding to transcription factor sites such as nuclear factor κ-B (NFκB) and activating protein 1 (AP-1), which can cause the formation of ET and TNF. Thus, stimulation of the ET-AR and TNFR thereby form an amplification loop. The present study demonstrated that selective ET-AR can directly modify TNFR activation.