Received 2001-12-25 Accepted 2002-02-28

The work was supported by the Natural Science Foundation of Zhejiang for Talents (No. RC99038) and Fund for Outstanding Young Scientists of Zhejiang University School of Medicine.

*Corresponding author. Tel: +86-571-87217146 Fax: +86-571-87217147 Email: xiaqiang@zjuem.zju.edu.cn

生理学报, Aug. 2002, 54 (4): 300~306

Acta Physiologica Sinica

研究论文

一氧化氮在铁诱导的大鼠心肌损伤中的作用

陈莹莹, 夏 强*, 曹春梅, 叶治国, 沈岳良, 王琳琳

浙江大学医学院生理教研室, 杭州 310031

摘 要: 采用Langendorff灌流大鼠心脏和酶解分离的心肌细胞为实验模型, 研究铁负荷下心肌损伤情况以及一氧化氮(NO)在铁诱导的心肌损伤中的地位。结果显示: (1)心肌铁负荷(Fe-HQ)可使分离心肌细胞舒张期细胞长度缩短、 收缩幅度和速度降低, 离体灌流心脏左室发展压(LVDP)、 ±dp/dtmax、 冠脉流量呈现双相变化; 冠脉流出液中乳酸脱氢酶(LDH)、 肌酸激酶(CK)释放量和心肌丙二醛(MDA)增高。 (2)NO的前体L-精氨酸(L-arginine, L-Arg)引起心肌细胞舒张期细胞长度缩短、 收缩幅度降低。离体灌流心脏LVDP、 冠脉流量、 和±dp/dtmax增高, 用K-H液复灌后可恢复正常。 (3)L-Arg预处理, 再行Fe-HQ灌流, 与单纯的L-Arg或Fe-HQ组相比, 心肌细胞舒张期细胞长度、 收缩幅度和速度减小; 离体灌流心脏LVDP、 ±dp/dtmax、 心率和冠脉流量明显下降, 冠脉流出液中LDH、 CK增加。 (4)Nω-硝基-L-精氨酸甲酯(L-NAME)和Fe-HQ合并灌流后, 与单纯Fe-HQ组相比, 心肌细胞舒张期细胞长度、 收缩幅度和速度增加。L-NAME可阻断Fe-HQ引起的LVDP、 左室舒张末压(LVEDP)和±dp/dtmax降低, 冠脉流出液中LDH、 CK增高。 (5)用Triton X-100短暂处理以去除冠脉内皮后, 与保留冠脉内皮的心肌相比, Fe-HQ引起的LVDP和±dp/dtmax的一过性增高现象被抑制, 但对复灌期LVDP和±dp/dtmax的改变无明显影响。上述实验结果表明, L-Arg可加重铁诱导的心肌损伤作用; L-NAME可通过抑制NOS减轻铁引起的心肌损伤, 其中冠脉内皮参与了铁的早期心肌作用。关键词: 铁; 心脏; 一氧化氮; L-精氨酸; N-硝基-L-精氨酸甲酯

学科分类号: Q46

Role of nitric oxide in iron-induced toxicity in rat hearts

CHEN Ying-Ying, XIA Qiang*, CAO Chun-Mei, YE Zhi-Guo, SHEN Yue-Liang, WANG Lin-Lin

Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310031

Abstract: The aim of the present study was to explore the effect of nitric oxide (NO) on iron-induced toxicity in rat hearts. Langendorff perfused rat heart and enzymatically isolated cardiomyocytes were used. It was shown that lipophilic Fe-HQ reduced the contractile amplitude, velocity and end-diastolic cell length in the cardiomyocyte, while the left ventricular developed pressure (LVDP), ±dp/dtmax, heart rate and coronary flow showed biphasic alterations, which increased in the first 2 min and then was followed by a decline in isolated perfused rat heart; the contents of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent and the malondialdehyde (MDA) in the myocardium were increased. L-arginine (L-Arg), an NO precursor, reduced the contractile amplitude and end-diastolic cell length in the cardiomyocyte; but reversibly increased LVDP, ±dp/dtmax, and coronary flow in isolated perfused rat heart. Pretreatment with L-Arg aggravated the Fe-HQ-induced decrease in contractile amplitude, velocity and end-diastolic cell length in the cardiomyocyte; LVDP, ±dp/dtmax, heart rate and coronary flow were significantly reduced in the perfused heart, and the levels of LDH and CK increased in the coronary effluent. In contrast, the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) blocked the Fe-HQ induced change in contractile amplitude, velocity and end-diastolic cell length in the cardio- myocyte; it inhibited the decrease in LVDP, LVEDP and ±dp/dtmax, and reduced the LDH and CK. Removing endothelial cells in coronary vessels attenuated the increase in LVDP and ±dp/dtmax at the beginning of Fe-HQ perfusion. It is suggested that L-Arg aggravates the iron-induced cardiac dysfunction, NO can mediate the iron-induced toxicity in heart, and endothelial cells in coronary vessels play an important role in the early stage of the effect of iron.

Key words: iron; heart; nitric oxide; L-arginine; NG-nitroarginine methyl ester