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

Abstract

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 B 2 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 B 2 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. Copyright © 2005 by the American Society for Clinical Pharmacology and Therapeutics.