Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis.
Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis.
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DOI：
10.1097/ccm.0b013e31819cecd6
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发表时间：
2009-04
影响因子：
8.8
通讯作者：
Levy RJ
中科院分区：
文献类型：
--
作者：
Verma R;Huang Z;Deutschman CS;Levy RJ
线粒体功能受损是脓毒症相关心肌抑制的潜在原因。细胞色素氧化酶（CcOX），电子传递链的末端氧化酶，在脓毒症心脏中被抑制。咖啡因通过增加环磷酸腺苷和蛋白激酶A活性来增加CcOX活性。我们假设，咖啡因将恢复心肌CcOX活性，增加心脏功能，并提高败血症患者的生存率。前瞻性随机对照研究。大学医院实验室。120只Sprague-Dawley雄性大鼠。雄性SD大鼠行盲肠结扎双穿刺术（CLP）或假手术。在24和48小时，大鼠接受腹膜内注射咖啡因（7.5 mg/kg，相当于1-1.5杯咖啡）或等体积的盐水。48小时注射后1小时，在分离的线粒体中测量稳态CcOX动力学活性，并将其标准化为柠檬酸合酶活性。使用离体大鼠心脏制备物评估心脏功能，并追踪存活至96小时。CLP显著降低心肌CcOX活性、耗氧量、左心室压和等容收缩（+dP/dt）和舒张（-dP/dt）时的压力。CLP后，咖啡因恢复了CcOX活性，并使左心室压力和±dP/dt向假手术值增加。与盐水注射相比，注射咖啡因的动物在CLP后的存活率显著提高。咖啡因可能是治疗脓毒症相关心肌抑制的一种新疗法。
Impaired mitochondrial function is a potential cause of sepsis-associated myocardial depression. Cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, is inhibited in the septic heart. Caffeine increases CcOX activity by increasing cyclic adenosine monophosphate and protein kinase A activity. We hypothesized that caffeine will restore myocardial CcOX activity, increase cardiac function, and improve survival during sepsis. Prospective randomized controlled study. University hospital-based laboratory. One hundred twenty Sprague-Dawley male rats. Sprague-Dawley male rats underwent cecal ligation and double puncture (CLP) or sham operation. At 24 and 48 hours, rats underwent intraperitoneal injection of either caffeine (7.5 mg/kg, the equivalent of 1-1.5 cups of coffee) or equal volume of saline. One hour following the 48-hour injection, steady-state CcOX kinetic activity was measured in isolated mitochondria and normalized to citrate synthase activity. Cardiac function was assessed using an isolated rat heart preparation and survival was tracked to 96 hours. CLP significantly decreased myocardial CcOX activity, oxygen consumption, left ventricular pressure, and pressure developed during isovolumic contraction (+dP/dt) and relaxation (-dP/dt). Caffeine restored CcOX activity and increased left ventricular pressure and ±dP/dt toward sham values following CLP. Survival significantly improved following CLP in caffeine-injected animals compared with saline injection. Caffeine may be a novel therapy to treat sepsis-associated myocardial depression.