Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha

被引:3
作者
Fukushima, Hisashi [1 ,2 ]
Oguchi, Takeshi [1 ]
Sato, Hiroaki [3 ]
Nakadate, Yosuke [1 ]
Sato, Tamaki [3 ]
Omiya, Keisuke [1 ]
Kawakami, Akiko [1 ]
Matsuoka, Toru [1 ]
Matsukawa, Takashi [1 ]
机构
[1] Univ Yamanashi, Fac Med, Dept Anesthesiol, 1110 Shimokato, Chuo City, Yamanashi 4093898, Japan
[2] Natl Hosp Org Mito Med Ctr, Dept Anesthesia, Sakuranosato 280, Ibaraki 3113193, Japan
[3] McGill Univ, Royal Victoria Hosp, Hlth Ctr, Dept Anesthesia, 1001 Decarie Blvd, Montreal, PQ H4A 3J1, Canada
基金
日本学术振兴会;
关键词
Protamine; Ulinastatin; Tumor necrosis factor-alpha; Myocardial depression; Isolated rat heart; ISCHEMIA-REPERFUSION INJURY; HIGH-DOSE ULINASTATIN; TNF-ALPHA; INFLAMMATORY RESPONSE; HEPARIN; SPHINGOSINE; LUNG;
D O I
10.1007/s00210-020-01983-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-alpha). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-alpha. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-alpha. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-alpha expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-alpha was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 +/- 4%. In contrast, the reduction in LV dP/dt max was 4 +/- 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-alpha in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-alpha alone reduced LV dP/dt max (- 21 +/- 14%). In contrast, when TNF-alpha was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 +/- 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-alpha synthesis and by directly preventing the cardiodepressant action of TNF-alpha.
引用
收藏
页码:373 / 381
页数:9
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