Morita K, Ihnken K, Buckberg G D, Matheis G, Sherman M P, Young H H
Department of Surgery, University of California, Los Angeles School of Medicine 90095-1741, USA.
J Thorac Cardiovasc Surg. 1995 Oct;110(4 Pt 2):1228-34. doi: 10.1016/s0022-5223(95)70009-9.
Previous studies show that (1) hypoxemia depletes immature myocardium of amino acid substrates and their replenishment improves ischemic tolerance, (2) reoxygenation on cardiopulmonary bypass causes oxygen-mediated damage without added ischemia, and (3) this damage may be related to the nitric oxide-L-arginine pathway that is affected by amino acid metabolism. This study tests the hypothesis that priming the cardiopulmonary bypass circuit with glutamate and aspartate limits reoxygenation damage. Of 22 immature Duroc-Yorkshire piglets (< 3 weeks old), five were observed over a 5-hour period (control), and five others underwent 30 minutes of CPB without hypoxemia (cardiopulmonary bypass control). Twelve others became hypoxemic by reducing ventilator inspired oxygen fraction to 6% to 7% (oxygen tension about 25 mm Hg) before reoxygenation on cardiopulmonary bypass for 30 minutes. Of these five were untreated (no treatment), and the cardiopulmonary bypass circuit was primed with 5 mmol/L glutamate and aspartate in seven others (treatment). Left ventricular function before and after bypass was measured by inscribing pressure-volume loops (end-systolic elastance). Myocardial conjugated diene levels were measured to detect lipid peroxidation, and antioxidant reserve capacity was tested by incubating cardiac muscle with the oxidant t-butylhydroperoxide to determine the susceptibility to subsequent oxidant injury. CPB (no hypoxemia) allowed complete functional recovery without changing conjugated dienes and antioxidant reserve capacity, whereas reoxygenation injury developed in untreated hearts. This was characterized by reduced contractility (elastance end-systolic recovered only 37% +/- 8%), increased conjugated diene levels (1.3 +/- 0.1 vs 0.7 +/- 0.1), and decreased antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30 malondialdehyde nmol/g protein at 2 mmol/L t-butylhydroperoxide*). In contrast, priming the cardiopulmonary bypass circuit with glutamate and aspartate resulted in significantly better left ventricular functional recovery (75% +/- 8% vs 37% +/- 8%), minimal conjugated diene production (0.8 +/- 0.1 vs 1.3 +/- 0.1), and improved antioxidant reserve capacity (726 +/- 27 vs 910 +/- 59 malondialdehyde nmol/g protein*) (*p < 0.05 vs cardiopulmonary bypass control). We conclude that reoxygenation of immature hypoxemic piglets by the initiation of cardiopulmonary bypass causes myocardial dysfunction, lipid peroxidation, and reduced tolerance to oxidant stress, which may increase vulnerability to subsequent ischemia (i.e., aortic crossclamping). These data suggest that supplementing the prime of cardiopulmonary bypass circuit with glutamate and aspartate may reduce these deleterious consequences of reoxygenation.
（1）低氧血症会耗尽未成熟心肌的氨基酸底物，而底物补充可改善缺血耐受性；（2）体外循环复氧会导致氧介导的损伤，且无额外缺血情况；（3）这种损伤可能与受氨基酸代谢影响的一氧化氮-L-精氨酸途径有关。本研究检验了以下假设：用谷氨酸和天冬氨酸预充体外循环回路可限制复氧损伤。在22头未成熟的杜洛克-约克夏仔猪（小于3周龄）中，5头在5小时内进行观察（对照组），另外5头在无低氧血症情况下进行30分钟的体外循环（体外循环对照组）。另外12头仔猪在体外循环复氧前，通过将呼吸机吸入氧分数降至6%至7%（氧分压约25 mmHg）造成低氧血症，复氧30分钟。其中5头未接受治疗（未治疗组），另外7头用5 mmol/L谷氨酸和天冬氨酸预充体外循环回路（治疗组）。通过绘制压力-容积环（收缩末期弹性）测量体外循环前后的左心室功能。测量心肌共轭二烯水平以检测脂质过氧化，并通过用氧化剂叔丁基过氧化氢孵育心肌来测试抗氧化储备能力，以确定对后续氧化损伤的易感性。体外循环（无低氧血症）可使功能完全恢复，且不改变共轭二烯和抗氧化储备能力，而未治疗的心脏会发生复氧损伤。其特征为收缩力降低（收缩末期弹性仅恢复37%±8%）、共轭二烯水平升高（1.3±0.1 vs 0.7±0.1）以及抗氧化储备能力降低（在2 mmol/L叔丁基过氧化氢时，丙二醛为910±59 vs 471±30 nmol/g蛋白质*）。相比之下，用谷氨酸和天冬氨酸预充体外循环回路可使左心室功能恢复明显更好（75%±8% vs 37%±8%）、共轭二烯生成最少（0.8±0.1 vs 1.3±0.1）以及抗氧化储备能力改善（丙二醛为726±27 vs 910±59 nmol/g蛋白质*）（*与体外循环对照组相比，p<0.05）。我们得出结论，未成熟低氧血症仔猪开始体外循环复氧会导致心肌功能障碍、脂质过氧化以及对氧化应激的耐受性降低，这可能会增加对后续缺血（即主动脉阻断）的易感性。这些数据表明，在体外循环回路预充液中补充谷氨酸和天冬氨酸可能会减少复氧的这些有害后果。
