一氧化氮在铁诱导的大鼠心肌损伤中的作用

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

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-argi-nine,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。

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 crea-tine 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 Nω-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.