Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts
Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts
复制标题
DOI：
10.1152/ajpheart.1999.276.6.h1861
复制
发表时间：
1999-06-01
影响因子：
4.8
通讯作者：
Schulz, R
中科院分区：
文献类型：
--
作者：
Ferdinandy, P;Panas, D;Schulz, R
我们研究了离体工作大鼠心脏机械功能随时间和蛋白质合成依赖性下降的机制。在存在或不存在蛋白质合成抑制剂环己亚胺（CX; 10 μ M）的情况下，用Krebs-Henseleit缓冲液灌注心脏120分钟。心脏功在60分钟内保持稳定，然后在60-120分钟灌注期间自发下降。与此同时，心肌诱导型一氧化氮合酶（iNOS）和黄嘌呤氧化酶（XO）活性增加，灌注液中二酪氨酸形成增加，二酪氨酸是过氧亚硝酸盐生成的一个指标。CX能明显减轻收缩功能的丧失，抑制iNOS、XO活性和二酪氨酸水平的升高。尽管对照组心脏的心脏工作下降，但两组三羧酸（TCA）循环活性和耗氧量之间的耦合保持不变。ATP、磷酸肌酸和糖原水平在对照组和CX组之间没有差异，在灌注120分钟后也没有差异。我们得出结论，在离体工作大鼠心脏中，心肌机械功能的延迟和自发丧失1)CX治疗减轻，2)伴随心肌iNOS和XO活性以及过氧亚硝酸盐生成的增加，3)不依赖于心肌ATP生成、心肌氧消耗或TCA循环乙酰辅酶a生成的直接损害，但可能是由于心脏利用ATP进行收缩工作的效率低下。
We examined the mechanism of the time- and protein synthesis-dependent decline in cardiac mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer for 120 min in the presence or absence of the protein synthesis inhibitor cycloheximide (CX; 10 mu M). Cardiac work remained stable for 60 min and then spontaneously decreased during 60-120 min of perfusion. This was accompanied by an increase in myocardial inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) activities and enhanced dityrosine formation in the perfusate, an indicator of peroxynitrite generation. CX markedly attenuated the loss in contractile function and prevented the increase in iNOS and XO activities and dityrosine level. Despite the decline in cardiac work in control hearts, the coupling between tricarboxylic acid (TCA) cycle activity and oxygen consumption remained constant in both groups. ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion. We concluded that the delayed and spontaneous loss in myocardial mechanical function in isolated working rat hearts is 1) attenuated by CX treatment, 2) accompanied by a concomitant increase in both iNOS and XO activities and peroxynitrite generation in the heart, and 3) not dependent on a direct impairment in myocardial ATP production, myocardial oxygen consumption, or TCA cycle acetyl-CoA production but may be due to an inefficiency of the heart to utilize ATP for contractile work.