The effects of levosimendan on liver blood flow, inflammation and mitochondrial dysfunction in sepsis

The aim of this study was to investigate the effects of levosimendan treatment on liver blood flow, inflammatory cytokine levels in liver tissue, mitochondrial dysfunction and apoptosis in an experimental sepsis modelThirty-eight adult male Wistar albino rats weighing 220-250 g were included in the study. Rats were randomly divided into 6 groups. Group I and II had the sham procedure. Group III, IV and V contracted intraabdominal sepsis via cecal ligation and puncture. After 24 hours of the procedures %5 dextrose infusion was administered intravenously in Group I and III. Levosimendan was given to Groups II and IV as a loading dose of 100 µgr/kg in 10 min, followed by continous infusion of 100 µgr/kg/h and to Group V as a loading dose of 200 µgr/kg in 10 min, followed by continous infusion of 200 µgr/kg/h for 4 hours. Blood pressure and heart rate values of each rat were recorded continously throughout the experiment. The rats were sacrificed by cervical dislocation after portal blood flow measurement by Doppler USG was monitored at the end of Levosimendan infusion. Hepatic tissues were then dissected to establish histological changes associated with the infusion. Tissue samples were stained with hematoxylin-eosin for examination of morphological alterations and sections were stained via TUNEL method in order to detect apoptotic cells. Hepatic tissue samples were also observed for TNF-?, IL-6, IL-10, Bcl-2, Bax, cytochrom C and caspase-3 by using indirect immunohistochemical techniqueDecrease in mean arterial pressure (MAP) and increase in heart rate (HR) after the bolus dose was demonstrated in levosimendan treated groups (II, IV, V). Portal blood flow was higher in Group IV when compared with the other groups. TUNEL positive cells were % 1.9±0.23, % 1.5±0.22, % 11.3±0.73, % 6.4±0.34, % 2.5±0.22 and % 0 in Groups I-VI respectively. There was no significant difference neither in comparison of Group I between Group II and V nor Group II compared with Group V and Group VI. (p>0.05) All other data comparisons between groups were observed to be statistically different. (p<0.001) In Group I, immunoreactivity of TNF-? was low, IL-6 and Bcl-2 was moderate and IL-6, Bax, cytochrom C and caspase-3 was negative. In Group II, immunoreactivity of TNF-?, IL-10 and Bax was low, IL-6, Bcl-2, cytochrom C and caspase-3 was negative. In Group III, immunoreactivity of TNF-? and caspase-3 was highly positive, IL-6, IL-l0 and cytochrom C was low, Bax was moderate and Bcl-2 was negative. In Group IV, immunoreactivity of TNF-?, Bax and caspase-3 was moderate, IL-6 and IL-10 was highly positive, Bcl-2 and cytochrom C was negative. In Group V, immunoreactivity of TNF-? and IL-6 was moderate in zone 3, low in zone 2 and negative in zone 3, IL-10 immunoreactivity was moderate except zone 3 that was highly positive, Bax and caspase-3 immunoreactivity was moderate, Bcl-2 and cytochrom C immunoreactivity was negative. In Group VI, immunoreactivity of TNF-? and Bax was extremely low, Bcl-2 was low, IL-10 was low in some of the zones and IL-6, cytochrom C and caspase-3 was negativeIn conclusion, this study demonstrated that in experimental sepsis model levosimendan decreases proinflammatory cytokine TNF-?; increases anti-inflammatory cytokines IL-6, IL-10 and reduces sepsis-induced apoptosis.