Abstract
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 Nω-nitro-l-arginine methyl ester (l-NAME) or the mitochondrial ATP-sensitive K+ channel (KATP 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-β-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 KATP channels and NO-related mechanisms.
Footnotes
This work was supported by Regione Piemonte (Ricerca Finalizzata) and Orion Pharma, Espoo, Finland.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- I/R
- ischemia/reperfusion
- NO
- nitric oxide
- NOS
- NO synthase
- eNOS
- endothelial NOS
- NAG
- N-acetyl-β-glucosaminidase
- l-NAME
- Nω-nitro-l-arginine methyl ester
- KATP channel
- ATP-sensitive K+ channel
- ROS
- reactive oxygen species
- TBA
- thiobarbituric acid
- TBARS
- TBA reactive substance
- GSH
- glutathione
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- SOD3
- superoxide dismutase 3
- 5-HD
- 5-hydroxydecanoate
- ERK
- extracellular signal-regulated kinase
- MDA
- malonyldyaldeide
- Levo
- levosimendan.
- Received March 2, 2012.
- Accepted May 4, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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