Morita K, Sherman M P, Buckberg G D, Ihnken K, Matheis G, Young H H, Ignarro L J
Department of Surgery, University of California, Los Angeles School of Medicine, USA.
J Thorac Cardiovasc Surg. 1995 Oct;110(4 Pt 2):1200-11. doi: 10.1016/s0022-5223(95)70006-4.
This study tests the hypothesis that nitric oxide, which is endothelial-derived relaxing factor, produces reoxygenation injury via the L-arginine-nitric oxide pathway in hypoxemic immature hearts when they are placed on cardiopulmonary bypass. Twenty 3-week-old piglets undergoing 2 hours of hypoxemia (oxygen tension about 25 mm Hg) on a ventilator were reoxygenated by initiating cardiopulmonary bypass (oxygen tension about 400 mm Hg). Five animals were not treated, whereas the pump circuit was primed with the nitric oxide-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg) in five piglets. L-Arginine, the substrate for nitric oxide, was administered in a fivefold excess (20 mg/kg), together with L-NAME in five piglets (L-NAME and L-arginine), and given alone in five other piglets (L-arginine). Five normoxemic, instrumented piglets served as a control group, and five others underwent 30 minutes of cardiopulmonary bypass without preceding hypoxemia. Left ventricular contractility was determined as end-systolic elastance by pressure-dimension loops. Myocardial conjugated dienes were measured as a marker of lipid peroxidation, and the antioxidant reserve capacity (malondialdehyde production in tissue incubated with t-butylhydroperoxide) was measured. Nitric oxide level was determined in coronary sinus plasma as its spontaneous oxidation product, nitrite. Cardiopulmonary bypass per se did not alter left ventricular contractility, cause lipid peroxidation, or lower antioxidant capacity. Reoxygenation without treatment depressed cardiac contractility (end-systolic elastance 38% +/- 12% of control*), raised nitric oxide (127% above hypoxemic values), increased conjugated dienes (1.3 +/- 0.2 vs 0.7 +/- 0.1, control*), and reduced antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30, control*). Inhibition of nitric oxide production by L-NAME improved end-systolic elastance to 84% +/- 12%,** limited conjugated diene elution (0.8 +/- 0.1 vs 1.3 +/- 0.2, no treatment**), and improved antioxidant reserve capacity (679 +/- 69 vs 910 +/- 59, no treatment**). Conversely, L-arginine counteracted these beneficial effects of L-NAME, because left ventricular function recovered only 24% +/- 6%,* conjugated dienes were 1.2 +/- 0.1,* and antioxidant reserve capacity was 826 +/- 70.* L-Arginine alone caused the same deleterious biochemical changes as L-NAME/L-arginine and resulted in 60% mortality. The close relationship between postbypass left ventricular dysfunction (percent end-systolic elastance) and myocardial conjugated diene production (r = 0.752) provides in vivo evidence that lipid peroxidation contributes to myocardial dysfunction after reoxygenation.(ABSTRACT TRUNCATED AT 400 WORDS)
内皮源性舒张因子一氧化氮，在低氧血症的未成熟心脏进行体外循环时，通过L-精氨酸-一氧化氮途径产生复氧损伤。20只3周龄仔猪在呼吸机上经历2小时低氧血症（氧分压约25 mmHg）后，通过启动体外循环进行复氧（氧分压约400 mmHg）。5只动物未接受治疗，5只仔猪的体外循环管道用一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME，4 mg/kg）预充。一氧化氮的底物L-精氨酸，以五倍过量（20 mg/kg）与L-NAME一起给予5只仔猪（L-NAME和L-精氨酸组），并单独给予另外5只仔猪（L-精氨酸组）。5只正常氧合、安装仪器的仔猪作为对照组，另外5只在无先前低氧血症的情况下进行30分钟体外循环。通过压力-容积环将左心室收缩力确定为收缩末期弹性。测量心肌共轭二烯作为脂质过氧化的标志物，并测量抗氧化储备能力（在与叔丁基过氧化氢孵育的组织中丙二醛的产生）。在冠状窦血浆中测定一氧化氮水平，以其自发氧化产物亚硝酸盐表示。体外循环本身并未改变左心室收缩力、引起脂质过氧化或降低抗氧化能力。未经治疗的复氧降低了心脏收缩力（收缩末期弹性为对照组的38%±12%），提高了一氧化氮水平（比低氧血症值高127%），增加了共轭二烯（1.3±0.2对0.7±0.1，对照组），并降低了抗氧化储备能力（910±59对471±30，对照组*）。L-NAME抑制一氧化氮生成使收缩末期弹性提高到84%±12%，限制了共轭二烯洗脱（0.8±0.1对1.3±0.2，未治疗），并改善了抗氧化储备能力（679±69对910±59，未治疗**）。相反，L-精氨酸抵消了L-NAME的这些有益作用，因为左心室功能仅恢复24%±6%，*共轭二烯为1.2±0.1，*抗氧化储备能力为826±70。*单独使用L-精氨酸引起与L-NAME/L-精氨酸相同的有害生化变化，并导致60%的死亡率。体外循环后左心室功能障碍（收缩末期弹性百分比）与心肌共轭二烯生成之间的密切关系（r = 0.752）提供了体内证据，表明脂质过氧化导致复氧后心肌功能障碍。（摘要截断于400字）
