Ishiyama S, Hiroe M, Nishikawa T, Abe S, Shimojo T, Ito H, Ozasa S, Yamakawa K, Matsuzaki M, Mohammed M U, Nakazawa H, Kasajima T, Marumo F
Second Department of Medicine, Tokyo Medical and Dental University, Japan.
Circulation. 1997 Jan 21;95(2):489-96. doi: 10.1161/01.cir.95.2.489.
Excess amounts of NO produced by an inducible NO synthase (iNOS) in response to cytokines may be cytotoxic and can be destructive to tissue. We investigated the role of NO in the development of myocardial damage and the effects of aminoguanidine (AG), an inhibitor of iNOS, on experimental autoimmune myocarditis in rats.
Autoimmune myocarditis was induced in 20 Lewis rats by injection of porcine cardiac myosin. Ten of the 20 rats were administered AG. The severity of myocarditis was evaluated by measuring the size of myocarditic lesion and serum levels of CK-MB. Serum NO levels were determined using the Cd/Cu method. Tissue specimens were immunohistochemically examined for iNOS and nitrotyrosine. Histopathological study revealed extensive myocardial destruction and massive inflammatory cell infiltration in AG-untreated rats but only focal mononuclear cell infiltration in AG-treated rats. The mean percent areas of inflammatory lesions in the untreated and treated rats were 56 +/- 13% and 3 +/- 2%, respectively (P < .001). NO levels were 102 +/- 23 and 25 +/- 9 IU/L, respectively (P < .01). CK-MB levels were 68 +/- 13 and 16 +/- 13 nmol/L, respectively (P < .01). Superoxide production as measured with an ex vivo monitoring system was also significantly decreased in the treated rats. Nitrotyrosine relating to the generation of peroxynitrite was detected through immunostaining in the inflammatory lesions of untreated rats but not in those of treated rats.
Excess amounts of NO produced by iNOS appear to contribute to the progression of myocardial damage in myocarditis. AG may prove to be useful in the treatment of myocarditis.
诱导型一氧化氮合酶（iNOS）响应细胞因子产生的过量一氧化氮（NO）可能具有细胞毒性，会对组织造成破坏。我们研究了NO在大鼠实验性自身免疫性心肌炎心肌损伤发展中的作用以及iNOS抑制剂氨基胍（AG）对其的影响。
通过注射猪心肌肌球蛋白，在20只Lewis大鼠中诱导自身免疫性心肌炎。20只大鼠中的10只给予AG。通过测量心肌病变大小和血清肌酸激酶同工酶（CK-MB）水平评估心肌炎的严重程度。采用镉/铜法测定血清NO水平。对组织标本进行免疫组织化学检测iNOS和硝基酪氨酸。组织病理学研究显示，未治疗的大鼠有广泛的心肌破坏和大量炎性细胞浸润，而接受AG治疗的大鼠只有局灶性单核细胞浸润。未治疗和治疗大鼠炎性病变的平均面积百分比分别为56±13%和3±2%（P<.001）。NO水平分别为102±23和25±9 IU/L（P<.01）。CK-MB水平分别为68±13和16±13 nmol/L（P<.01）。用体外监测系统测量，治疗大鼠的超氧化物产生也显著降低。通过免疫染色在未治疗大鼠的炎性病变中检测到与过氧亚硝酸盐生成相关的硝基酪氨酸，而在治疗大鼠中未检测到。
iNOS产生的过量NO似乎促进了心肌炎心肌损伤的进展。AG可能对心肌炎治疗有用。
