辅酶Q10预处理改善心脏对缺血耐受性的三方机制解析。

Crestanello J A, Kamelgard J, Lingle D M, Mortensen S A, Rhode M, Whitman G J

Division of Cardiothoracic Surgery, Medical College of Pennsylvania, Philadelphia 19129, USA.

J Thorac Cardiovasc Surg. 1996 Feb;111(2):443-50. doi: 10.1016/s0022-5223(96)70455-5.

Coenzyme Q10, which is involved in mitochondrial adenosine triphosphate production, is also a powerful antioxidant. We hypothesize that coenzyme Q10 pretreatment protects myocardium from ischemia reperfusion injury both by its ability to increase aerobic energy production and by protecting creatine kinase from oxidative inactivation during reperfusion. Isolated hearts (six per group) from rats pretreated with either coenzyme Q10, 20 mg/kg intramuscularly and 10 mg/kg intraperitoneally (treatment) or vehicle only (control) 24 and 2 hours before the experiment were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes of reperfusion. Developed pressure, contractility, compliance, myocardial oxygen consumption, and myocardial aerobic efficiency were measured. Phosphorus 31 nuclear magnetic resonance (31P-NMR) spectroscopy was used to determine adenosine triphosphate and phosphocreatine concentrations as a percentage of a methylene diphosphonic acid standard. Hearts were assayed for myocardial coenzyme Q10 and myocardial creatine kinase activity at end equilibration and at reperfusion. Treated hearts showed higher myocardial coenzyme Q10 levels (133 +/- 5 micrograms/gm ventricle versus 117 +/- 4 micrograms/gm ventricle, p < 0.05). Developed pressure at end reperfusion was 62% +/- 2% of equilibration in treatment group versus 37% +/- 2% in control group, p < 0.005. Preischemic myocardial aerobic efficiency was preserved during reperfusion in treatment group (0.84 +/- 0.08 mm Hg/(microliter O2/min/gm ventricle) vs 1.00 +/- 0.08 mm Hg/(microliter O2/min/gm ventricle) at equilibration, p = not significant), whereas in the control group it fell to 0.62 +/- 0.07 mm Hg/(microliter O2/min/gm ventricle, p < 0.05 vs equilibration and vs the treatment group at reperfusion. Treated hearts showed higher adenosine triphosphate and phosphocreatine levels during both equilibration (adenosine triphosphate 49% +/- 2% for the treatment group vs 33% +/- 3% in the control group, p < 0.005; phosphocreatine 49% +/- 3% in the treatment group vs 35% +/- 3% in the control group, p < 0.005) and reperfusion (adenosine triphosphate 18% +/- 3% in the treatment group vs 11% +/- 2% in the control group, CTRL p < 0.05; phosphocreatine 45% +/- 2% in the treatment group vs 23% +/- 3% in the control group, p < 0.005). Creatine kinase activity in treated hearts at end reperfusion was 74% +/- 3% of equilibration activity vs 65% +/- 2% in the control group, p < 0.05). Coenzyme Q10 pretreatment improves myocardial function after ischemia and reperfusion. This results from a tripartite effect: (1) higher concentration of adenosine triphosphate and phosphocreatine, initially and during reperfusion, (2) improved myocardial aerobic efficiency during reperfusion, and (3) protection of creatine kinase from oxidative inactivation during reperfusion.

辅酶Q10参与线粒体三磷酸腺苷的生成，也是一种强大的抗氧化剂。我们推测，辅酶Q10预处理可通过增加有氧能量生成以及在再灌注期间保护肌酸激酶免受氧化失活的能力，来保护心肌免受缺血再灌注损伤。在实验前24小时和2小时，分别用辅酶Q10（20mg/kg肌肉注射和10mg/kg腹腔注射，治疗组）或仅用赋形剂（对照组）对大鼠进行预处理，然后将分离的心脏（每组6个）进行15分钟的平衡、25分钟的缺血和40分钟的再灌注。测量心脏的舒张末压、收缩性、顺应性、心肌耗氧量和心肌有氧效率。采用磷31核磁共振（31P-NMR）光谱法测定三磷酸腺苷和磷酸肌酸浓度，并以亚甲基二膦酸标准物的百分比表示。在平衡末期和再灌注末期对心脏进行心肌辅酶Q10和心肌肌酸激酶活性检测。治疗组心脏的心肌辅酶Q10水平较高（心室为133±5μg/g，对照组为117±4μg/g，p<0.05）。再灌注末期的舒张末压在治疗组为平衡末期的62%±2%，而对照组为37%±2%，p<0.005。治疗组在再灌注期间保留了缺血前的心肌有氧效率（再灌注时为0.84±0.08mmHg/（μl O2/min/g心室），平衡时为1.00±0.08mmHg/（μl O2/min/g心室），p无显著性差异），而对照组则降至0.62±0.07mmHg/（μl O2/min/g心室），与平衡时相比以及与再灌注时的治疗组相比，p<0.05。治疗组心脏在平衡期（治疗组三磷酸腺苷为49%±2%，对照组为33%±3%，p<0.005；磷酸肌酸治疗组为49%±3%，对照组为35%±3%，p<0.005）和再灌注期（治疗组三磷酸腺苷为18%±3%，对照组为11%±2%，p<0.05；磷酸肌酸治疗组为45%±2%，对照组为23%±3%，p<0.005）的三磷酸腺苷和磷酸肌酸水平均较高。再灌注末期治疗组心脏的肌酸激酶活性为平衡期活性的74%±3%，而对照组为65%±2%，p<0.05）。辅酶Q10预处理可改善缺血再灌注后的心肌功能。这是由三方效应导致的：（1）在初始阶段和再灌注期间三磷酸腺苷和磷酸肌酸浓度较高；（2）再灌注期间心肌有氧效率提高；（3）再灌注期间保护肌酸激酶免受氧化失活。