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


CONCLUSIONS
Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.
Pretorius
Mias
M
Veterans Affairs Medical Center and Department of Anesthesiology, Vanderbilt University School of Medicine, 560 Robinson Research Building, Nashville, TN 37232, USA. mias.pretorius@vanderbilt.edu
Scholl
Frank G
FG
McFarlane
Julie A
JA
Murphey
Laine J
LJ
Brown
Nancy J
NJ
D000368:Aged; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D065094:Bradykinin B2 Receptor Antagonists; D002315:Cardiopulmonary Bypass; D004311:Double-Blind Method; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006494:Heparin Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007022:Hypotension / Q000139:chemically induced* / Q000188:drug therapy*; D007705:Kinins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011183:Postoperative Complications / Q000139:chemically induced* / Q000188:drug therapy*; D011479:Protamines / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000627:therapeutic use
D065094:Bradykinin B2 Receptor Antagonists; D006494:Heparin Antagonists; D007705:Kinins; D011479:Protamines; C065679:icatibant; D001920:Bradykinin