Wakefield T W, Bies L E, Wrobleski S K, Bolling S F, Stanley J C, Kirsh M M
Department of Surgery, University of Michigan Medical Center, Ann Arbor.
Ann Surg. 1990 Oct;212(4):387-93; discussion 394. doi: 10.1097/00000658-199010000-00001.
The myocardial effects of protamine, with and without heparin, were documented in this investigation. Isolated rabbit hearts (n = 30) were retrograde perfused with Krebs-Ringers bicarbonate solution aerated with 95% O2/5% CO2 through the aortic root (37 C, 80 mmHg). Developed left ventricular blood pressure, heart rate, coronary artery flow, contractility as reflected by peak +dp/dt, oxygen extraction (a-vO2), and oxygen consumption (VO2) were measured at baseline and continuously throughout the experiment. Protamine (25 micrograms, 50 micrograms, and 250 micrograms per mL of perfusate) was circulated in the Krebs-Ringers buffer to hearts perfused without heparin (groups I, II, and III) or hearts perfused with heparin added to the buffer solution, 0.1 IU/1.0 microgram protamine (groups IV, V, and VI). Blood pressure 4 minutes after protamine was less in groups III (-23 mmHg) and VI (-28 mmHg) than in groups I (-6 mmHg), II (-18 mmHg), IV (-1 mmHg), and V (-7 mmHg). Heart rate changes (beats/minute) at 4 minutes revealed similar dose-dependent reductions (III and VI: -51, -55; II and V: -36, -36; and I and IV: -20, -16, respectively). Coronary artery flow at 4 minutes was slightly increased in groups III (9 mL/minute) and VI (15 mL/minute), but was relatively unchanged in the other groups. Decreases in contractility were apparent in all groups 4 minutes after protamine was started: group I, -14%; II, -16%; III, -30%; IV, -7%; V, -15%; and VI, -34%. Similarly declines in oxygen extraction and consumption were noted in all groups at the same time period and were greater in groups III (-53%, -44%) and VI (-55%, -49%) than in groups I (-25%, -26%), II (-15%, -12%), IV (-48%, -49%) and V (-15%, -18%), with p less than or equal to 0.05 or p less than or equal to 0.01 compared to baseline. Three of ten hearts exposed to high-dose protamine stopped beating after 5 minutes. This investigation establishes, for the first time, that protamine has dose- and time-specific adverse effects on cardiac contractility. In addition protamine decreases myocardial a-vO2 and VO2. These changes may contribute to certain adverse events accompanying the clinical administration of protamine.
本研究记录了有肝素和无肝素时鱼精蛋白对心肌的影响。将30只离体兔心通过主动脉根部用含95% O₂/5% CO₂的 Krebs - Ringer 碳酸氢盐溶液进行逆行灌注（37℃，80 mmHg）。在基线时以及整个实验过程中持续测量左心室舒张末压、心率、冠状动脉血流量、反映收缩性的峰值 +dp/dt、氧摄取量（a - vO₂）和耗氧量（VO₂）。鱼精蛋白（每毫升灌注液25微克、50微克和250微克）在 Krebs - Ringer 缓冲液中循环至未加肝素灌注的心脏（I、II和III组）或缓冲溶液中添加了肝素（0.1 IU/1.0微克鱼精蛋白）灌注的心脏（IV、V和VI组）。鱼精蛋白给药4分钟后，III组（-23 mmHg）和VI组（-28 mmHg）的血压低于I组（-6 mmHg）、II组（-18 mmHg）、IV组（-1 mmHg）和V组（-7 mmHg）。4分钟时心率变化（次/分钟）显示出类似的剂量依赖性降低（III组和VI组分别为-51、-55；II组和V组分别为-36、-36；I组和IV组分别为-20、-16）。4分钟时冠状动脉血流量在III组（9毫升/分钟）和VI组（15毫升/分钟）略有增加，但其他组相对未变。在开始给予鱼精蛋白4分钟后，所有组的收缩性均明显降低：I组，-14%；II组，-16%；III组，-30%；IV组，-7%；V组，-15%；VI组，-34%。同样，在同一时间段内所有组的氧摄取量和耗氧量均下降，III组（-53%，-44%）和VI组（-55%，-49%）比I组（-25%，-26%）、II组（-15%，-12%）、IV组（-48%，-49%）和V组（-15%，-18%）下降更明显，与基线相比p≤0.05或p≤0.01。暴露于高剂量鱼精蛋白的十颗心脏中有三颗在5分钟后停止跳动。本研究首次证实，鱼精蛋白对心脏收缩性具有剂量和时间特异性的不良影响。此外，鱼精蛋白降低心肌的a - vO₂和VO₂。这些变化可能导致鱼精蛋白临床应用时出现某些不良事件。
