Pretorius Mias, Scholl Frank G, McFarlane Julie A, Murphey Laine J, Brown Nancy J
Veterans Affairs Medical Center and Department of Anesthesiology, Vanderbilt University School of Medicine, 560 Robinson Research Building, Nashville, TN 37232, USA.
Clin Pharmacol Ther. 2005 Nov;78(5):477-85. doi: 10.1016/j.clpt.2005.08.010.
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.
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.
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).
Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.
在体外循环（CPB）期间接受肝素治疗的患者中使用鱼精蛋白会引起低血压。鱼精蛋白抑制羧肽酶N介导的缓激肽降解，缓激肽是一种可引起血管舒张和组织型纤溶酶原激活剂（t-PA）释放的肽。本研究检验了主要假设，即阻断缓激肽B（2）受体会减轻鱼精蛋白相关的低血压。
我们对16例接受择期心脏手术且需要CPB并术前服用血管紧张素转换酶（ACE）抑制剂的成年男性患者进行了一项前瞻性、双盲、随机研究，因为ACE抑制会增加CPB期间的缓激肽浓度。在给予鱼精蛋白之前，将受试者随机分为接受生理盐水（N = 8）或缓激肽B（2）受体拮抗剂HOE 140（100μg/kg，N = 8）。术中以及给予鱼精蛋白前后测量平均动脉压（MAP）和t-PA活性。
在生理盐水组中，给予鱼精蛋白后缓激肽浓度显著升高（从6.0±1.3至10.0±1.6 fmol/mL，P = 0.043），HOE 140组中也是如此（从6.5±1.8至14.3±4.6 fmol/mL，P = 0.042）。在生理盐水组中，鱼精蛋白显著降低MAP（从69.8±4.4 mmHg降至平均个体最低点56.1±2.6 mmHg，P = 0.031），但缓激肽受体拮抗作用减弱了这种效应（HOE 140组中从74.3±3.7 mmHg降至平均个体最低点69.6±1.2 mmHg，P = 0.545）。因此，在输注鱼精蛋白期间，生理盐水组的MAP显著低于HOE 140组（P = 0.002）。在给予HOE 140期间，t-PA活性显著降低（从3.59±0.31降至1.67±0.42 IU/mL，P = 0.001），而在生理盐水组中未降低（从2.12±0.48降至1.44±0.36 IU/mL，P = 0.214）。同样，在HOE 140组中给予鱼精蛋白期间，t-PA活性显著降低（从1.67±0.42降至0.77±0.26 IU/mL，P = 0.038），而在生理盐水组中未降低（从1.44±0.36降至0.99±0.26 IU/mL，P = 0.132）。
在接受ACE抑制剂治疗的患者中，缓激肽增加通过其B（2）受体导致鱼精蛋白相关的低血压。
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