Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha
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ORIGINAL ARTICLE
Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha Hisashi Fukushima 1,2 & Takeshi Oguchi 1 & Hiroaki Sato 3 & Yosuke Nakadate 1 & Tamaki Sato 3 & Keisuke Omiya 1 & Akiko Kawakami 1 & Toru Matsuoka 1 & Takashi Matsukawa 1 Received: 29 July 2020 / Accepted: 29 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. 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-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α 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-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (− 21 ± 14%). In contrast, when TNF-α 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-α synthesis and by directly preventing the cardiodepressant action of TNF-α. Keywords Protamine . Ulinastatin . Tumor necrosis factor-α . Myocardial depression . Isolated rat heart
Introduction Protamine, a poly-cationic peptide used for reversing the anticoagulating effects of heparin, is associated with systemic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01983-2) contains supplementary material, which is available to authorized users. * Takeshi Oguchi [email protected] 1
Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-City, Yamanashi 409-3898, Japan
2
Department of Anesthesia, National Hospital Organization Mito Medical Center, Sakuranosato 280, Ibaraki-machi, Higashiibaraki-gun, Ibaraki 311-3193, Japan
3
Department of Anesthesia, Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec H4A 3J1, Canada
hypotension, cardiac depression, bradycardia, and pulmonary arterial hypertension (Boer et al. 2018; Oguchi et al. 2001). Oguchi et al. have shown that the ni
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