Levosimendan pretreatment improves survival of septic rats after partial hepatectomy and suppresses iNOS induction in cytokine-stimulated hepatocytes

Tatsuma Sakaguchi,Hideyuki Matsushima,Tadayoshi Okumura,Masaki Kaibori,Yuki Hashimoto,Hidehiko Hishikawa,Mikio Nishizawa

doi:10.1038/s41598-019-48792-z

Tatsuma Sakaguchi, Hideyuki Matsushima + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-48792-z

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Abstract

We evaluated the survival effects and biochemical profiles of levosimendan in septic rats after partial hepatectomy and investigated its effects in cultured hepatocytes. Thirty-two rats underwent 70% hepatectomy and were randomised equally into four groups, followed by lipopolysaccharide (LPS) injection (250 µg/kg, i.v.) after 48 h. Levosimendan was given (i.p.) 1 h before LPS injection [group (A) levosimendan 2 mg/kg; (B) 1; (C) 0.5; (D) vehicle]. Survival at 7 days was increased significantly in group A compared with that in group D [A: 63%; B: 38%; C: 13%; D: 0%]. In serum, levosimendan decreased the level of tumour necrosis factor-α, interleukin (IL)-1β, IL-6 and nitric oxide (NO). In remnant livers, levosimendan inhibited inducible nitric oxide synthase (iNOS) gene expression. In primary cultured rat hepatocytes stimulated by IL-1β, levosimendan suppressed NO production by inhibiting iNOS promoter activity and stability of its mRNA.

Highlights

Levosimendan is a calcium sensitiser licensed in numerous countries to treat decompensated heart failure[1]
We have less than 10% failure rate of PH/LPS model during the induction of anaesthesia and laparotomy, there was no rat to be lost during the interval between randomisation after laparotomy and LPS injection
Pretreatment of levosimendan increased the survival of PH/LPS-model rats in a dose-dependent fashion, though a significant difference was only found between group A and group D by post hoc analysis

Summary

Introduction

Levosimendan is a calcium sensitiser licensed in numerous countries to treat decompensated heart failure[1]. LPS has a direct effect on macrophages (or Kupffer cells) to activate nuclear factor (NF)-κB, which induces expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS) The latter produces an excess of NO, which has been implicated in tissue injury and assumed to be one of the triggers leading to septic shock and multiple-organ failure[23]. We reported that fibronectin[18], pirfenidone[19], edaravone[20] and sivelestat[21] improved survival and prevented liver injury in PH/LPS-model rats These agents commonly exerted survival benefits if they were administered before LPS injection and had inhibitory effects on iNOS induction in hepatocytes[24,25,26]. In primary cultured rat hepatocytes, interleukin (IL)-1β stimulates production of iNOS and NO markedly in the absence of other cytokines[27], and prevention of expression of those proinflammatory mediators is a reliable indicator of liver protection[28]

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