Vesnarinone restores contractility and calcium handling in early endotoxemia.
Vesnarinone restores contractility and calcium handling in early endotoxemia.
复制标题
Vesnarinone 可恢复早期内毒素血症的收缩性和钙处理能力。
DOI：
10.1161/01.cir.102.suppl_3.iii-365
复制
发表时间：
2000
期刊：
影响因子：
37.8
通讯作者：
McGowanJr,FX
中科院分区：
文献类型：
--
作者：
Takeuchi,K;delNido,PJ;Poutias,DN;Cowan,DB;Munakata,M;McGowanJr,FX
内毒素（脂多糖，LPS）是全身炎症反应的触发因素。我们以前已经发现，当在LPS之前给予维司力农和氨力农时，可以防止细胞因子的产生和LPS相关的心功能障碍。我们测试的假设，维司力农将改善细胞内Ca 2+处理和钙激活的收缩力发作后，endotoxemia.Methods和Results-Adult兔接受了一个团注LPS或车辆。90分钟后静脉给予维司力农（3 mg/kg）。LPS给药后2小时，以分离的Langendorff模式灌注心脏。用荧光光谱法测定心肌细胞内钙浓度（CaI）和心肌细胞内钙瞬变下降速率（τCa），评价左室最大发展压（±dp/dt）、氧耗量（MV ~ o ~ 2）和速率×压力乘积。LPS组左室最大发展压和±dp/dt明显降低。这些都是完全恢复vesnarinone。LPS心脏的舒张期钙清除明显较慢（τCa增加），这也被维司力农纠正;然而，LPS心脏的细胞溶质钙超载特征仅部分改善。减少机械效率低下（率-压力产品的比率，以MV今O2）和肌丝的敏感性Cai也显着改善vesnarinone. Conclusions急性内毒素血症引起收缩蛋白钙不敏感，氧浪费，和钙循环异常。在救援模式下给予维司力农，使LPS诱导的心肌功能障碍正常化，并部分恢复异常的钙循环。虽然这些作用的机制需要进一步澄清，但似乎药物如维司力农可能有助于治疗炎症诱导的心肌功能障碍。
Background—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 Ca2+handling and calcium-activated contractile force after the onset of endotoxemia.Methods and Results—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 (MV̇o2), and rate×pressure product were evaluated in conjunction with fluorescent spectroscopic determinations of intracellular calcium concentrations (Cai) and the rate of Caitransient decline during diastole (τCa). 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 τCa) 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 MV̇o2) and myofilament sensitivity to Caiwere also significantly improved by vesnarinone.Conclusions—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.