Selective endothelin-A receptor inhibition after cardiac surgery: a safety and feasibility study.
BACKGROUND
Increased synthesis and release of the bioactive peptide endothelin has been shown to change hemodynamics and postoperative recovery after cardiac surgery. However, the clinical effects of selective interruption of endothelin signaling have not been studied. Because the endothelin-A (ET-A) receptor subtype is the primary cardiovascular effector for endothelin, this study used the ET-A receptor antagonist sitaxsentan sodium (TBC11251Na) to evaluate: (1) dose-dependent changes in pulmonary artery pressure (PAP) and pulmonary (PVRI) and systemic (SVRI) vascular resistance index in patients undergoing on-pump coronary revascularization; and (2) whether ET-RA administration was associated with increased adverse events.


METHODS
Patients (n = 44, age, 62 +/- 1 years) were randomized to receive vehicle (n = 9) or different bolus infusions of ET-A receptor antagonist: 0.1 (n = 9), 0.5 (n = 9) 1.0 (n = 9), and 2.0 mg/kg (n = 8) at separation from cardiopulmonary bypass (CPB). Adverse events were tabulated until hospital discharge. Results were expressed as changes from a composite baseline value, or from time 0 due to a high degree of intrapatient measurement variability in the postoperative period.


RESULTS
PAP increased by 27% +/- 13% from baseline (19 +/- 1 mm Hg) in the vehicle group at 6 hours post-CPB (p < 0.05). PAP fell from this post-CPB vehicle value in a dose-dependent manner with the ET-A receptor antagonist; with a significant reduction observed at 2 mg/kg (7% +/- 8% increase from baseline, p < 0.05). PVRI was reduced by 28.6% +/- 16% from baseline (249 +/- 22 dyn x s x cm(-5) x m(-2)) in the 2 mg/kg ET-A receptor antagonist group at 30 minutes post-CPB and remained reduced up to 6 hours post-CPB (p < 0.05). SVRI was reduced from baseline (2770 +/- 106 dyn x s x cm(-5) x m(-2)) by 51% +/- 6% in the 2.0 mg/kg ET-A receptor antagonist group at 30 minutes post-CPB (p < 0.05) and remained reduced up to 6 hours post-CPB. A total of 203 adverse events were tabulated in the postoperative period and were equally distributed across the five treatment groups, with no direct attributions to ET-A receptor antagonist treatment.


CONCLUSIONS
This unique study demonstrates that heightened endothelin-A receptor activation contributes to hemodynamic changes in patients after CPB. Selective inhibition of the endothelin receptor system can be successfully and safely performed in patients undergoing cardiac surgery and thereby reveals a potential, and clinically relevant therapeutic target.
Ikonomidis
John S
JS
Division of Cardiothoracic Surgery, Cardiothoracic Surgical Laboratory, Medical University of South Carolina, Charleston, South Carolina 29425, USA. ikonomij@musc.edu
Hilton
Ebony J
EJ
Payne
Kimberly
K
Harrell
April
A
Finklea
Laura
L
Clark
Leslie
L
Reeves
Scott
S
Stroud
Robert E
RE
Leonardi
Amy
A
Crawford
Fred A
FA
Spinale
Francis G
FG
D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D002315:Cardiopulmonary Bypass; D002317:Cardiovascular Agents / Q000494:pharmacology*; D001026:Coronary Artery Bypass; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D005240:Feasibility Studies; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D011651:Pulmonary Artery / Q000503:physiopathology; D013876:Thiophenes / Q000494:pharmacology*; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects
D002317:Cardiovascular Agents; D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; D013876:Thiophenes; C106276:sitaxsentan