Fremantle Heart Institute, Fremantle Hospital, School of Surgery and Pathology, University of Western Australia, Fremantle, WA, Australia.
Inflamm Res. 2010 Nov;59(11):907-13. doi: 10.1007/s00011-010-0239-8. Epub 2010 Aug 6.
Tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of cardiovascular disease and sepsis-associated cardiac dysfunction. Although initially described solely as a lipopolysaccharide (LPS)-induced macrophage product, evidence exists that cardiac myocytes themselves produce substantial amounts of TNF-α in response to ischemia as well as LPS. The use of phosphodiesterase inhibitors has been shown to decrease LPS-induced TNF-α elaboration. The aim of the present study was to determine the effect of diazepam (Type IV phosphodiesterase inhibitor) on (1) myocardial function and (2) coronary vascular flow after LPS-induced endotoxic shock in an isolated rat heart model.
Endotoxemia was induced by intraperitoneal LPS administration in adult male Wistar rats. Hearts were isolated after 6 h and perfused in a working mode with oxygenated Krebs-Henseleit buffer at 37°C. Diazepam was mixed with Krebs-Henseleit buffer and administered (3.0 μg/ml) for 20 min.
LPS-treated hearts showed depressed cardiac function and reduced coronary flow. Myocardial functional parameters (LVDP, +dP/dt, -dP/dt, RPP) and coronary flow (ml/min) were significantly (p < 0.01) improved by diazepam administration.
These findings suggest that diazepam can salvage myocardial function and undo coronary vascular constriction in the endotoxemic rat heart. These findings are clinically relevant to the treatment of cardiovascular depression caused by endotoxic shock.
肿瘤坏死因子-α（TNF-α）与心血管疾病和脓毒症相关的心功能障碍的发病机制有关。尽管最初仅被描述为脂多糖（LPS）诱导的巨噬细胞产物，但有证据表明心肌细胞本身在缺血以及 LPS 反应中会产生大量的 TNF-α。已经证明使用磷酸二酯酶抑制剂可以减少 LPS 诱导的 TNF-α的产生。本研究的目的是确定地西泮（IV 型磷酸二酯酶抑制剂）对 LPS 诱导的内毒素休克后（1）心肌功能和（2）冠状动脉血流的影响，使用离体大鼠心脏模型。
通过腹腔内 LPS 给药诱导内毒素血症，成年雄性 Wistar 大鼠。在 6 小时后，心脏被分离并在 37°C 的含氧 Krebs-Henseleit 缓冲液中以工作模式灌注。地西泮与 Krebs-Henseleit 缓冲液混合并给药（3.0μg/ml）20 分钟。
LPS 处理的心脏显示出心脏功能降低和冠状动脉流量减少。心肌功能参数（LVDP、+dP/dt、-dP/dt、RPP）和冠状动脉流量（ml/min）通过地西泮给药显著改善（p<0.01）。
这些发现表明地西泮可以挽救内毒素血症大鼠的心肌功能并消除冠状动脉血管收缩。这些发现与治疗由内毒素休克引起的心血管抑制具有临床相关性。
