Thielmann Matthias, Dörge Hilmar, Martin Claus, Belosjorow Sergej, Schwanke Uwe, van De Sand Anita, Konietzka Ina, Büchert Astrid, Krüger Arne, Schulz Rainer, Heusch Gerd
Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Germany.
Circ Res. 2002 Apr 19;90(7):807-13. doi: 10.1161/01.res.0000014451.75415.36.
Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-alpha, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-microm diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6+/-4.9% (mean+/-SD) at baseline to 4.1+/-3.7% at 8 hours after microembolization. Leukocyte count, TNF-alpha, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3+/-2.6% at baseline) with intracoronary administration of L-NAME (20.8+/-3.4%) and 17.7+/-2.3% at 8 hours after microembolization; TNF-alpha and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7+/-4.6% at baseline) with intravenous administration of NOE (19.5+/-5.7%) and 16.4+/-6.3% at 8 hours after microembolization; TNF-alpha, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-alpha, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.
冠状动脉微栓塞会导致进行性心肌功能障碍，肿瘤坏死因子-α（TNF-α）参与其中。TNF-α通过涉及一氧化氮（NO）和/或鞘氨醇的信号转导发挥作用。因此，我们在麻醉的犬身上诱导冠状动脉微栓塞，并研究NO、TNF-α和鞘氨醇在不断发展的收缩功能障碍中的作用及顺序。4只假手术犬作为对照组（第1组）。11只犬接受安慰剂（第2组），6只犬在通过向左旋冠状动脉每毫升血流中注入3000个微球（直径42微米）诱导微栓塞前接受一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME，第3组），6只犬接受神经酰胺酶抑制剂N-油酰乙醇胺（NOE，第4组）。第1组的后收缩期壁增厚（PWT）保持不变，但第2组从基线时的20.6±4.9%（平均值±标准差）逐渐下降至微栓塞后8小时的4.1±3.7%。微栓塞后的心肌中白细胞计数、TNF-α和鞘氨醇含量增加。在第3组中，冠状动脉内给予L-NAME时PWT保持不变（基线时为20.3±2.6%），微栓塞后8小时为20.8±3.4%；TNF-α和鞘氨醇含量未增加。在第4组中，静脉给予NOE时PWT也保持不变（基线时为20.7±4.6%），微栓塞后8小时为19.5±5.7%；TNF-α含量增加，但鞘氨醇含量未增加。在所有组中，整个实验过程中全身血流动力学、前收缩期壁增厚和局部心肌血流均保持不变。NO、TNF-α和鞘氨醇的信号转导级联因果性地参与了冠状动脉微栓塞诱导的进行性收缩功能障碍。
