A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine‐related hypotension after cardiopulmonary bypass

• Published in: Clinical pharmacology and therapeutics 2005-11, Vol.78 (5), p.477-485
• Main Authors: Pretorius, Mias, Scholl, Frank G., McFarlane, Julie A., Murphey, Laine J., Brown, Nancy J.
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Bradykinin - analogs & derivatives; Bradykinin - therapeutic use; Bradykinin B2 Receptor Antagonists; Cardiopulmonary Bypass; Double-Blind Method; Female; Fibrinolysis - drug effects; Hemodynamics - drug effects; Heparin Antagonists - adverse effects; Heparin Antagonists - therapeutic use; Humans; Hypotension - chemically induced; Hypotension - drug therapy; Kinins - blood; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Pilot Projects; Postoperative Complications - chemically induced; Postoperative Complications - drug therapy; Protamines - adverse effects; Protamines - antagonists & inhibitors; Protamines - therapeutic use
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2005.08.010

Background The administration of protamine to patients who received heparin during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the carboxypeptidase N‐mediated degradation of bradykinin, a peptide that causes vasodilation and tissue‐type plasminogen activator (t‐PA) release. This study tests the primary hypothesis that blocking the bradykinin B2 receptor would attenuate protamine‐related hypotension. Methods We conducted a prospective, double‐blind, randomized study in 16 adult male patients undergoing elective cardiac surgery requiring CPB and taking an angiotensin‐converting enzyme (ACE) inhibitor preoperatively, because ACE inhibition increases bradykinin concentrations during CPB. Subjects were randomized to receive either saline solution (N = 8) or the bradykinin B2 receptor antagonist HOE 140 (100 μg/kg, N = 8) before the administration of protamine. Mean arterial pressure (MAP) and t‐PA activity were measured intraoperatively and before and after protamine administration. Results Protamine administration caused a significant increase in bradykinin concentrations in the saline solution group (from 6.0 ± 1.3 to 10.0 ± 1.6 fmol/mL, P: = .043), as well as the HOE 140 group (from 6.5 ± 1.8 to 14.3 ± 4.6 fmol/mL, P: = .042). Protamine significantly decreased MAP in the saline solution group (from 69.8 ± 4.4 mm Hg to a mean individual nadir of 56.1 ± 2.6 mm Hg, P: = .031), but bradykinin receptor antagonism blunted this effect (from 74.3 ± 3.7 mm Hg to a mean individual nadir of 69.6 ± 1.2 mm Hg in the HOE 140 group, P: = .545). Hence, during protamine infusion, MAP was significantly lower in the saline solution group compared with the HOE 140 group (P: = .002). t‐PA activity decreased significantly during administration of HOE 140 (from 3.59 ± 0.31 to 1.67 ± 0.42 IU/mL, P: = .001) but not during saline solution (from 2.12 ± 0.48 to 1.44 ± 0.36 IU/mL, P: = .214). Similarly, t‐PA activity decreased significantly during protamine administration in the HOE 140 group (from 1.67 ± 0.42 to 0.77 ± 0.26 IU/mL, P: = .038) but not in the saline solution group (from 1.44 ± 0.36 to 0.99 ± 0.26 IU/mL, P: = .132). Conclusion Increased bradykinin contributes to protamine‐related hypotension through its B2 receptor in ACE inhibitor‐treated patients. Clinical Pharmacology & Therapeutics (2005) 78, 477–485; doi: 10.1016/j.clpt.2005.08.010