Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury
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Published on: April 2, 2017
Mohamed A Ibrahim1, Seham A Abdel-Gaber1, Entesar F Amin1
1Departments of Pharmacology, Faculty of medicine, Minia University, El-Minia, Egypt.
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.
Insights
Levosimendan protects against liver ischemia-reperfusion injury (IRI) by activating cyclooxygenase (COX), modulating nitric oxide (NO), and opening potassium channels. These mechanisms contribute to its hepatoprotective effects in rats.
Area of Science:
- Pharmacology
- Hepatology
- Biochemistry
Background:
- Ischemia-reperfusion injury (IRI) is a significant cause of liver damage.
- Levosimendan shows promise in preventing IRI.
- The precise mechanisms of levosimendan's protective effects require further elucidation.
Purpose of the Study:
- To investigate the role of nitric oxide (NO), cyclooxygenase (COX) enzymes, and K-ATP channels in levosimendan's protective effect against liver IRI in rats.
- To assess the impact of levosimendan on oxidative stress and inflammatory markers.
Main Methods:
- Rats subjected to liver IRI were treated with levosimendan alone or in combination with COX inhibitors (indomethacin, celecoxib), NO synthase inhibitor (L-NNA), or K-ATP channel blocker (glibenclamide).
- Liver injury was assessed via serum ALT levels and histopathology.
- Oxidative stress markers, TNF-α, iNOS, eNOS, and caspase-3 expression were analyzed.
Main Results:
- Levosimendan significantly attenuated liver IRI, reducing serum ALT levels and improving histopathological findings.
- The protective effect was linked to reduced oxidative stress, decreased TNF-α, and modulated iNOS, eNOS, and caspase-3 expression.
- Partial attenuation of levosimendan's hepatoprotection occurred with COX, NO synthase, or K-ATP channel inhibition.
Conclusions:
- Levosimendan exerts a hepatoprotective effect against IRI in rats.
- This protection is, at least partly, mediated by the activation of COX-1, modulation of NO pathways, and opening of K-ATP channels.
