Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR) injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment) or 24 hours (late pretreatment) before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR) as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (pearly = 0.02; plate = 0.005), AST (pearly = 0.02; plate = 0.004) and less DNA damage by TUNEL test (pearly = 0.05; plate = 0.034) and PAR positivity (pearly = 0.02; plate = 0.04). Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection

Levosimendan Administration in Limb Ischemia: Multicomponent Signaling Serving Kidney Protection

AIMS AND OBJECTIVES: Acute renal failure is a severe complication of lower extremity major arterial reconstructions, which could even be fatal. Levosimendan is a dual-acting positive inotropic and vasodilatory agent, which is suspected to have protective effects against cardiac ischemia. However, there is no data available on lower limb or remote organ ischemic injuries therefore the aim of the study was to investigate the effect of levosimendan on lower limb ischemia-reperfusion injury and the corollary renal dysfunction. METHODS: Male Wistar rats underwent 180 min bilateral lower limb ischemia followed by 4 or 24 hours of reperfusion. Intravenous Levosimendan was administered continuously (0.2mug/bwkg/min) throughout the whole course of ischemia and the first 3h of reperfusion. Results were compared with sham-operated and ischemia-reperfusion groups. Hemodynamic monitoring was performed by invasive arterial blood pressure measurement. Kidney and lower limb muscle microcirculation was registered by a laser Doppler flowmeter. After 4h and 24h of reperfusion, serum, urine and histological samples were collected. RESULTS: Systemic hemodynamic parameters and microcirculation of kidney and the lower limb significantly improved in the Levosimendan treated group. Muscle viability was significantly preserved 4 and 24 hours after reperfusion. At the same time, renal functional laboratory tests and kidney histology demonstrated significantly less expressive kidney injury in Levosimendan groups. TNF-alpha levels were significantly less elevated in the Levosimendan group 4 hours after reperfusion. CONCLUSION: The results claim a protective role for Levosimendan administration during major vascular surgeries to prevent renal complications

Posztkondicionálás kisérletes vizsgálata vékonybél ischaemiás-reperfusiós modelljében

INTRODUCTION: The ischemic-reperfusion injury of the intestine, which occurs as a consequence of circulatory redistribution or occlusion of the superior mesenteric artery, is associated with high mortality rates. Postconditioning may reduce ischemic-reperfusion damage in such cases. Effects of this new surgical method were investigated in rats. METHODS: Male Wistar rats underwent 60 minutes of superior mesenteric artery occlusion in four groups: sham-operated, control and two postconditioned groups with different algorithms. Postconditioning was performed immediately at the beginning of reperfusion, by repetitive cycles of reperfusion and reocclusion. 3 cycles of 1 minute and 6 cycles of 10 seconds were applied according to groups. Intestinal microcirculation was followed by laser Doppler flowmetry. Blood and tissue samples were taken after 60 minutes of reperfusion. Histological analayses of the small intestine, measurement of serum necroenzyme levels and IL-6, mesenterial venous blood gas analyses were preformed and antioxidant state of the mucosa was investigated. RESULTS: The microcirculation during the reperfusion showed significant improvement in both postconditioned groups. Histological damage, necroenzyme and IL-6 levels were significantly reduced, while antioxidant state was improved in the postconditioned groups. CONCLUSION: Postconditioning was capable of increasing the guts chance to survive ischemic-reperfusion injury caused by superior mesenteric artery occlusion

Mean arterial pressure.

<p>Blood pressure elevated significantly after aortic clamping and remained elevated throughout the ischemic period in the IR (ischemia-reperfusion) group (broken line). Levosimendan treatment withheld this elevation during ischemia (unbroken line). At the onset of reperfusion a significant drop occurred, but after that, mean arterial pressure increased and then remained elevated in both IR and Levosimendan groups without significant difference between the groups. Sham operated group is marked with a dotted line. Values are expressed as means ± SD, †: p<0.01 vs. Sham, ‡: p<0.001 vs. Sham, §: p<0.001 vs. IR.</p

Muscle microcirculation measured with laser Doppler flowmeter.

<p>Measured flux is expressed as a percentage of the baseline flux before the aortic clamping. Flux dropped at the onset of aortic occlusion in both the ischemia-reperfusion (IR, marked with a broken line) and Levosimendan (unbroken line) groups. After release of the aortic occlusion, microcirculation increased to about 100% of baseline flux in the Levoismendan group, while in IR group flux reached only 80% of the baseline measurements. Sham operated group is marked with a dotted line. Values are expressed as means ± SD, ‡: p<0.001 vs. Sham, $: p<0.01 vs. IR, §: p<0.001 vs. IR.</p

Kidney cortex microcirculation measured with laser Doppler flowmeter.

<p>Measured flux is expressed as a percentage of the baseline flux before the aortic clamping. Flux remained at the baseline level after clamping of the infrarenal aorta in all three animal groups. After revascularization of the limbs, a constant impairment of the kidney cortex microcirculatory flux was observed in the ischemia-reperfusion (IR) group (marked with a broken line), while flux was preserved in the Levosimendan (unbroken line) and the Sham (dotted line) groups. Values are expressed as means ± SD, ‡: p<0.001 vs. Sham, §: p<0.001 vs. IR.</p