title: Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury.
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.
authors.affiliation: Departments of Pharmacology, Faculty of medicine, Minia University, El-Minia, Egypt. Electronic address: maim69@yahoo.com.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ibrahim
authors.affiliation: Departments of Pharmacology, Faculty of medicine, Minia University, El-Minia, Egypt.
authors.forename: Seham A
authors.initials: SA
authors.lastname: Abdel-Gaber
authors.affiliation: Departments of Pharmacology, Faculty of medicine, Minia University, El-Minia, Egypt.
authors.forename: Entesar F
authors.initials: EF
authors.lastname: Amin
authors.affiliation: Departments of Pharmacology, Faculty of medicine, Minia University, El-Minia, Egypt.
authors.forename: Salwa A
authors.initials: SA
authors.lastname: Ibrahim
authors.affiliation: Departments of Pathology, Faculty of medicine, Minia University, Egypt.
authors.forename: Rehab K
authors.initials: RK
authors.lastname: Mohammed
authors.affiliation: Departments of Pharmacology, Faculty of medicine, Minia University, El-Minia, Egypt.
authors.forename: Aly M
authors.initials: AM
authors.lastname: Abdelrahman
mesh_terms: D000818:Animals; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000077464:Simendan
chemical_list: D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan
keywords: Liver ischemia-reperfusion injury; levosimendan