Takeuchi K, del Nido P J, Poutias D N, Cowan D B, Munakata M, McGowan F X
Departments of Anesthesiology and Cardiac Surgery and the Anesthesia/Critical Care Medicine Laboratory, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Circulation. 2000 Nov 7;102(19 Suppl 3):III365-9. doi: 10.1161/01.cir.102.suppl_3.iii-365.
Endotoxin (lipopolysaccharide, LPS) is a trigger of the systemic inflammatory response. We have previously found that vesnarinone and amrinone, when given before LPS, prevented cytokine production and LPS-related cardiac dysfunction. We tested the hypothesis that vesnarinone would improve intracellular Ca(2+) handling and calcium-activated contractile force after the onset of endotoxemia.
Adult rabbits received a bolus injection of LPS or vehicle. Vesnarinone (3 mg/kg) was given intravenously 90 minutes later. Two hours after LPS administration, hearts were perfused in the isolated Langendorff mode. Peak left ventricular developed pressure, +/-dp/dt, oxygen consumption (MVO(2)), and ratexpressure product were evaluated in conjunction with fluorescent spectroscopic determinations of intracellular calcium concentrations (Ca(i)) and the rate of Ca(i) transient decline during diastole (tauCa). Peak left ventricular developed pressure and +/-dp/dt were significantly lower in the LPS group. These were completely restored by vesnarinone. There was significantly slower diastolic calcium removal (increased tauCa) in LPS hearts that was also corrected by vesnarinone; however, the cytosolic calcium overload characteristic of LPS hearts was only partially improved. Reduced mechanical inefficiency (the ratio of rate-pressure product to MVO(2)) and myofilament sensitivity to Ca(i) were also significantly improved by vesnarinone.
Acute endotoxemia caused contractile protein calcium insensitivity, oxygen wastage, and abnormal calcium cycling. Vesnarinone, given in the rescue mode, normalized LPS-induced myocardial dysfunction and partially restored abnormal calcium cycling. Although the mechanisms responsible for these effects require further clarification, it appears that agents such as vesnarinone may be useful to treat inflammatory-induced myocardial dysfunction.
内毒素（脂多糖，LPS）是全身炎症反应的触发因素。我们之前发现，在给予LPS之前使用维司力农和氨力农可预防细胞因子产生及LPS相关的心脏功能障碍。我们检验了以下假设：在内毒素血症发作后，维司力农可改善细胞内Ca(2+)处理及钙激活的收缩力。
成年兔接受LPS或赋形剂的单次注射。90分钟后静脉注射维司力农（3mg/kg）。给予LPS两小时后，心脏在离体Langendorff模式下灌注。结合荧光光谱法测定细胞内钙浓度（Ca(i)）及舒张期Ca(i)瞬变下降速率（tauCa），评估左心室舒张末压峰值、+/-dp/dt、耗氧量（MVO(2)）及心率-压力乘积。LPS组左心室舒张末压峰值及+/-dp/dt显著降低。维司力农可使其完全恢复。LPS心脏舒张期钙清除明显减慢（tauCa增加），维司力农也可纠正这一情况；然而，LPS心脏的胞质钙超载特征仅得到部分改善。维司力农还显著改善了机械效率降低（心率-压力乘积与MVO(2)的比值）及肌丝对Ca(i)的敏感性。
急性内毒素血症导致收缩蛋白对钙不敏感、氧耗增加及钙循环异常。在挽救模式下给予维司力农可使LPS诱导的心肌功能障碍恢复正常，并部分恢复异常的钙循环。尽管导致这些效应的机制需要进一步阐明，但维司力农这类药物似乎可用于治疗炎症诱导的心肌功能障碍。
