Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury

Mohamed A. Ibrahim, Seham A. Abdel-Gaber, Entesar F. Amin, Salwa A. Ibrahim, Rehab K. Mohammed, Aly M. Abdelrahman

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15 Citations (Scopus)

Abstract

Ischemia-reperfusion injury (IRI) is an important cause of liver damage in many clinical situations. Levosimendan is a promising therapy for prevention of IRI. The present work investigated the possible contribution of nitric oxide (NO), cyclooxygenase (COX) enzymes, and adenosine triphosphate sensitive potassium channel (K-ATP) in the protective effect of levosimendan in liver IRI in rats. Rats were divided into 7 groups. Sham-operated group (negative control group); IR-nontreated group (positive control group), levosimendan-treated group (treated with levosimendan); indomethacin, nonselective COX inhibitor,+levosimendan group (cotreated with indomethacin+levosimendan); celecoxib (selective COX-2 inhibitor)+levosimendan group; L-NNA (Nitro- ω-L-arginine, nonselective NO synthase inhibitor)+levosimendan group; and glibenclamide (K-ATP blocker)+levosimendan group. Liver injury was evaluated biochemically (by serum level of alanine aminotransferase (ALT)) as well as by histopathology. Hepatic tissue content of oxidative stress markers, tumor necrosis factor-alpha (TNF-α), along with immunohistochemical expression of induced NO synthase (iNOS), endothelial NO synthase (eNOS), and caspase-3 in hepatic tissue were assayed. The study showed that levosimendan attenuated liver IRI as evidenced by a decrease in serum ALT level and confirmed by histopathology. The protective effect of levosimendan was associated with modulation of oxidative stress, TNF-α, iNOS, eNOS, and caspase-3. The hepatoprotective effect of levosimendan was partially attenuated by pretreatment by either nonselective COX inhibitor, NOS inhibitor, or K-ATP channel blocker; indicating that the hepatoprotective effect of levosimendan was attributed, at least in part to activation of COX-1, modulation of NO, and opening of K-ATP channel.

Original languageEnglish
Pages (from-to)64-73
Number of pages10
JournalEuropean Journal of Pharmacology
Volume741
DOIs
Publication statusPublished - Oct 15 2014

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Keywords

  • levosimendan
  • Liver ischemia-reperfusion injury

ASJC Scopus subject areas

  • Pharmacology

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