Neural mechanisms of cardiotoxicity of novel cytotoxins produced by methicillin-resistant Staphylococcus aureus

近年来，由于抗生素的过度使用，老年人、肿瘤患者和手术患者发生严重机会性感染的病例有增加的趋势。其中，耐甲氧西林金黄色葡萄球菌（MRSA）感染是严重的，有时是致命的。然而，药物治疗MRSA中毒患者的策略尚未建立。千叶大学医学院的Noda教授和他的同事们从重症监护病房住院的患者中分离并纯化了两种新的MRSA细胞毒素（HL-细胞毒素和HS-细胞毒素）。我们研究了新型MRSA细胞毒素在小鼠和豚鼠心脏组织中引起的电生理变化。静脉注射MRSA毒素可引起小鼠心电图改变，如PR间期延长、QRS波群增宽、心动过缓和心律失常。用常规微电极技术在离体豚鼠乳头肌上进行的电生理学实验表明，超灌注MRSA毒素可引起静息膜电位和动作电位时程的降低和发展性张力（DT）的增加。DT的增加被α和β肾上腺素能拮抗剂预处理阻断，并通过重复应用毒素而减弱。这些结果暗示神经机制参与MRSA毒素的心脏毒性。我们观察到类似的假单胞菌毒素和MRSA毒素的分子生物学技术（GST-HS-细胞毒素）在小鼠的心脏毒性作用。因此，MRSA毒素可能通过神经机制产生致死性心脏毒性。然而，需要进一步的研究来阐明MRSA毒素心脏毒性的精确细胞机制。

Recently, number of severe opportunistic infections in aged, cancer-bearing or operated patients in hospital is increasing probubly due to excessive use of antibiotics. Among them, methicillin-resistant Staphylococcus aureus (MRSA) infection is sever and sometimes lethal. However, strategy for the medical treatmant of patients suffering from MRSA intoxication has not been established. Professor Noda and his colleagues, Chiba University School of Medicine, have isolated and purified two novel cytotoxins (HL-cytotoxin and HS-cytotoxin) of MRSA from patient hospitalized at an intensive care unit. We studied electrophysiological changes in cardiac tissue induced by the novel MRSA cytotoxins in mice and guinea pigs. Intravenous injection of the MRSA toxins produced marked ECG changes, such as prolongation of PR interval, widening in QRS complex, bradycardia and arrhythmias, in mice. Electrophysiological experiments using cnventional microelectrode techniques in isolated guinea-pig papillary muscles revealed that decreases in resting membrane potential and action potential duration and an indcrease in developed tensions (DT) were inuced by supefusion of the MRSA-toxins. The increase in DT was blocked by pre-treatment with alpha and beta adrenergic antagonists and was attenuated by repeated application of the toxins. These results imply the involvement of neural mechanism in cardiotoxicity of the MRSA toxins. We observed similar cardiotoxic effects with Pseudomonas toxin and MRSA toxin produced by molecular biological techniques (GST-HS-cytotoxin) in mice. Thus, MRSA toxin may produce lethal cardiotixicity through neural mechanisms. However, further studies are needed to clarify precise cellular mechanism (s) of the cardiotoxicity of MRSA toxins.