Hirono S, Islam M O, Nakazawa M, Yoshida Y, Kodama M, Shibata A, Izumi T, Imai S
Department of Pharmacology, Niigata University School of Medicine, Japan.
Circ Res. 1997 Jan;80(1):11-20. doi: 10.1161/01.res.80.1.11.
Excessive NO produced by an inducible NO synthase (iNOS) has been implicated in many types of immune-associated disorders of the cardiovascular system, but it remains to be determined whether NO plays a role in myocarditis. Thus, the significance of iNOS expression in the development of experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, was investigated. Lewis rats were immunized with cardiac myosin and were killed 7, 14, 21, 28, and 49 days after immunization. The development of severe myocarditis was observed on days 14, 21, and 28 in association with significant deterioration of hemodynamics determined by cardiac catheterization, which peaked on day 21. In parallel with histological severity of myocarditis and deterioration of cardiac performance, iNOS activity in the heart measured by [14C]L-citrulline formation was markedly increased on days 14, 21, and 28. The expression of iNOS was confirmed by immunoblotting and was localized to the infiltrating inflammatory cells found in the vicinity of necrotic myocytes by immunohistochemical analysis. Aminoguanidine, a selective inhibitor of iNOS, significantly decreased the iNOS activity (1.04 +/- 0.37 compared with 29.1 +/- 8.62 pmol.min-1.mg protein-1 in untreated myosin-immunized rats, P < .01) and effectively attenuated histopathological changes of EAM on day 21. Hemodynamic parameters were also improved from 64 +/- 3 to 89 +/- 3 mm Hg for mean blood pressure, from 80 +/- 2 to 113 +/- 4 mm Hg for left ventricular systolic pressure, from 7.8 +/- 0.3 to 3.2 +/- 0.3 mm Hg for left ventricular end-diastolic pressure, from 2867 +/- 137 to 4180 +/- 102 mm Hg/s for +dP/dt, and from 2717 +/- 132 to 4180 +/- 184 mm Hg/s for -dP/dt (P < .01). The values after aminoguanidine treatment were not significantly different from the control values. These results suggest an important role for NO in mediating pathophysiological changes in myocarditis of autoimmune origin.
诱导型一氧化氮合酶（iNOS）产生的过量一氧化氮（NO）与多种心血管系统免疫相关疾病有关，但NO是否在心肌炎中起作用仍有待确定。因此，研究了iNOS表达在实验性自身免疫性心肌炎（EAM，人类巨细胞性心肌炎的动物模型）发病过程中的意义。用心肌肌球蛋白免疫Lewis大鼠，并在免疫后7、14、21、28和49天处死。在第14、21和28天观察到严重心肌炎的发展，同时通过心导管检查确定血流动力学显著恶化，在第21天达到峰值。与心肌炎的组织学严重程度和心脏功能恶化同时，通过[14C]L-瓜氨酸生成法测定的心脏中iNOS活性在第14、21和28天显著增加。通过免疫印迹证实了iNOS的表达，并通过免疫组织化学分析将其定位在坏死心肌细胞附近的浸润性炎症细胞中。氨基胍是一种iNOS的选择性抑制剂，它显著降低了iNOS活性（未处理的肌球蛋白免疫大鼠中为29.1±8.62 pmol·min-1·mg蛋白-1，而氨基胍处理组为1.04±0.37，P <.01），并在第21天有效减轻了EAM的组织病理学变化。血流动力学参数也得到改善，平均血压从64±3 mmHg升至89±3 mmHg，左心室收缩压从80±2 mmHg升至113±4 mmHg，左心室舒张末期压力从7.8±0.3 mmHg降至3.2±0.3 mmHg，+dP/dt从2867±137 mmHg/s升至4180±102 mmHg/s，-dP/dt从2717±132 mmHg/s升至4180±184 mmHg/s（P <.01）。氨基胍处理后的数值与对照值无显著差异。这些结果表明NO在介导自身免疫性心肌炎的病理生理变化中起重要作用。
