Modulation of Programmed Forms of Cell Death by Intracoronary Levosimendan During Regional Myocardial Ischemia in Anesthetized Pigs

Grossini, Elena; Caimmi, Philippe Primo; Platini, Francesca; Molinari, Claudio; Uberti, Francesca; Cattaneo, Marco; Valente, Guido; Mary, David A.S.G.; Vacca, Giovanni; Tessitore, Luciana

doi:10.1007/s10557-010-6217-0

Cited by 22 publications

(30 citation statements)

References 45 publications

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“…Moreover, Western blot analysis revealed decreased eNOS phosphorylation in ischemic kidneys, which was prevented by levosimendan administration. Again, these results are in agreement with previous findings showing that eNOSderived NO is responsible for maintaining physiological renal hemodynamic performance and function regarding the involvement of NO in the effects elicited by levosimendan (Grossini et al, 2009(Grossini et al, , 2010Caimmi et al, 2011;Uberti et al, 2011).…”

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confidence: 93%

“…In addition, renal blood flow at the end of reperfusion almost returned to control values without differences compared with what was observed in other groups of animals. Thus, the present findings confirmed previous observations in heart and cardiomyocytes (Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011) regarding the effects of levosimendan as an antioxidant, antiapoptotic, and prosurvival agent.…”

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confidence: 92%

“…Moreover, levosimendan has been shown to protect cardiomyocytes from apoptotic cell death caused by I/R injuries (Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011). The anti-ischemic effects elicited by levosimendan could arise from its action on mitochondrial K ATP channels (Kaheinen et al, 2001;Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011), the modulation of NO release (Grossini et al, 2005(Grossini et al, , 2009, and mitochondrial function (Kaheinen et al, 2001;Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011). Taken together, these findings would suggest that renal protective effects caused by levosimendan occur not only through hemodynamic improvement but also by direct cellular action.…”

Section: Introductionmentioning

confidence: 96%

“…Hence, levosimendan, in addition to improving myocardial contraction and exerting vasodilation, has been demonstrated to have the potential to protect against I/R damage through a preconditioning-like effect (Kersten et al, 2000;Soeding et al, 2011) and the reduction of inflammatory and oxidative stress profiles (Avgeropoulou et al, 2005). Moreover, levosimendan has been shown to protect cardiomyocytes from apoptotic cell death caused by I/R injuries (Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011). The anti-ischemic effects elicited by levosimendan could arise from its action on mitochondrial K ATP channels (Kaheinen et al, 2001;Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011), the modulation of NO release (Grossini et al, 2005(Grossini et al, , 2009, and mitochondrial function (Kaheinen et al, 2001;Grossini et al, 2010;Caimmi et al, 2011b;Uberti et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs

Grossini¹,

Molinari²,

Pollesello³

et al. 2012

J Pharmacol Exp Ther

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Ischemia/reperfusion (I/R) injury is an important cause of acute renal failure because of oxidative, inflammatory, and apoptotic mechanisms. The aim of the present study was to examine any possible protective effects of levosimendan in an in vivo pig model of renal I/R injury. In 40 anesthetized pigs (eight groups of five pigs each), I/R was induced by clamping-reopening the left renal artery. During ischemia, in three groups of pigs, levosimendan and the multiorgan preservation solution Custodiol, alone or in combination with levosimendan, were infused in the renal artery. In two other groups of animals, levosimendan in combination with Custodiol was administered after the intrarenal nitric-oxide (NO) synthase blocker N -nitro-L-arginine methyl ester (L-NAME) or the mitochondrial ATP-sensitive K ϩ channel (K ATP channel) inhibitor 5-hydroxydecanoate (5-HD). In the other animals, saline, L-NAME, or 5-HD were administered alone. Throughout the experiments, urinary N-acetyl-␤-glucosaminidase (NAG) release was measured, and renal function was assessed. Moreover, renal biopsy samples were taken for the detection of apoptosis and tissue peroxidation. In pigs treated with levosimendan or the combination of levosimendan and Custodiol, NAG, peroxidation, and apoptotic markers were lower than in animals treated with Custodiol alone. In addition, renal function was better preserved, and cell survival and antioxidant systems were more activated. All beneficial effects were prevented by L-NAME and 5-HD. In conclusion, levosimendan alone or in combination with Custodiol exerted better protection against renal I/R injuries than Custodiol alone through antioxidant, antiapoptotic, and prosurvival actions depending on mitochondrial K ATP channels and NO-related mechanisms.

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confidence: 93%

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confidence: 92%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs

Grossini¹,

Molinari²,

Pollesello³

et al. 2012

J Pharmacol Exp Ther

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“…A number of in vitro and in vivo studies including models of acute coronary ischemia and cardiac dysfunction showed that levosimendan provided myocardial protection by inducing preconditioning of the myocardium against peri-operative I/R injury and by involving apoptotic pathway (32)(33)(34)(35)(36). The fi ndings in Masson Trichrome staining and immunohistochemical evaluation showed that portal acinus Zone 3 was the most affected area from I/R injury and then zones 2 and 1, respectively.…”

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confidence: 99%

The histopathological effects of levosimendan on liver injury induced by myocardial ischemia and reperfusion

Oktar¹,

Amac²,

Elmas³

et al. 2015

BLL

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Abstract:Background: The aim of this study was to evaluate the histological and immunohistochemical effects of levosimendan on liver injury induced by myocardial ischemia and reperfusion (I/R) in a rat model. Methods: Twenty-four male Wistar Albino rats were randomly divided into the four groups: Group C (Control, n = 6), Group I/R (n = 6), Group BI (I/R group treated with levosimendan before ischemia, n = 6), and Group AI (I/R group treated with levosimendan after ischemia, n = 6). Myocardial I/R was induced by ligation of the left anterior descending coronary artery for 30 min followed by two hours of reperfusion in I/R and I/R+Levosimendan groups. At the end of the study, liver tissue samples were obtained for histopathological and immunohistochemical examination. Results: Masson Trichrome staining revealed signifi cant hepatocyte degeneration and necrosis most marked in portal acinus Zone 3, especially around the central veins in Group I/R. Histopathological changes in Group AI were more similar to the changes in Group I/R. Milder hepatocellular degeneration was found in Group BI, when compared to groups I/R and AI. Immunohistochemical score was found to be signifi cantly higher in Group I/R compared to groups C, BI and AI (p < 0.0001). The scores in groups BI and AI were found to be similar (p = 0.068). Conclusion: Levosimendan ameliorates liver injury induced by myocardial IR, especially when administered before induction of ischemia (Fig. 9, Ref. 37). Text in PDF www.elis.sk.

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Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats

et al. 2014

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As in other organs, oxidative stress-induced injury and cell death may result from free oxygen radical-dependent mechanisms and alterations in signal transduction pathways leading to apoptosis. Among the new suggested therapies for injuries caused by oxidative stress, the use of levosimendan has been reported to be quite promising. In the present study, we aimed to examine the protective effects of levosimendan against liver oxidative stress in anesthetized rats and to analyze the involvement of mitochondrial adenosine triphosphate-dependent potassium (mitoK ATP ) channels and nitric oxide (NO). In 50 anesthetized rats, liver ischemia/reperfusion (I/R) was performed via nontraumatic portal occlusion. In some animals, levosimendan was infused into the portal vein at the onset of reperfusion, whereas other rats received the vehicle only. Moreover, in some rats, levosimendan was given after the intraportal administration of L-Nx-nitro-arginine methyl ester (L-NAME) or 5-hydroxydecanoate (5HD). The portal vein blood flow was measured, and blood samples were taken for the determination of transaminases, thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH); liver biopsy samples were used for B cell lymphoma 2-associated X protein, caspase-9, Akt, and endothelial nitric oxide synthase (eNOS) activation through western blotting. Also, caspase-3 activity was measured. In rats, I/R caused an increase in apoptotic markers, transaminases, and TBARS and a decrease in GSH and Akt activation. Levosimendan administration was able to counteract oxidative damage and apoptosis in a dose-dependent way and to increase GSH, Akt, and eNOS activation. All effects of levosimendan were abolished by pretreatment with L-NAME and 5HD. In conclusion, the results of the present study show that levosimendan can exert protection against ischemic liver damage through mechanisms related to NO production and mitoK ATP channel function. These data provide interesting perspectives into the use of levosimendan in hepatic surgery and transplantation. Liver Transpl 20:361-375, 2014. V C 2013 AASLD.Received August 1, 2013; accepted November 9, 2013.Oxidative stress has been implicated as a mechanism of liver injury due to ischemia/reperfusion (I/R) and can occur in a variety of clinical contexts, including hepatectomy, transplantation, hypovolemic shock, cardiogenic shock, and low-output syndrome.1-5 The precise mechanisms of I/R-induced liver injury have Abbreviations: 5HD, 5-hydroxydecanoate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bax, B cell lymphoma 2-associated X protein; eNOS, endothelial nitric oxide synthase; GSH, reduced glutathione; H&E, hematoxylin and eosin; I/R, ischemia/reperfusion; L-NAME, L-Nx-nitro-arginine methyl ester; MDA, malondialdehyde; mitoK ATP , mitochondrial adenosine triphosphate-dependent potassium; NO, nitric oxide; p-Akt, phosphorylated Akt; p-Bax, phosphorylated B cell lymphoma 2-associated X protein; p-caspase-9, phosphorylated caspase-9; p-eNOS, phosphorylated endotheli...

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Modulation of Programmed Forms of Cell Death by Intracoronary Levosimendan During Regional Myocardial Ischemia in Anesthetized Pigs

Abstract: Such effects of intracoronary levosimendan bolus administration during regional myocardial ischemia indicate the occurrence of cardio-protection by modulation of programmed form of cell death.

Cited by 22 publications

References 45 publications

Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs

Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs

The histopathological effects of levosimendan on liver injury induced by myocardial ischemia and reperfusion

Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats

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