title: Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs.
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 N(ω)-nitro-L-arginine methyl ester (L-NAME) or the mitochondrial ATP-sensitive K(+) 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-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 K(ATP) channels and NO-related mechanisms.
authors.affiliation: Department of Translational Medicine, University East Piedmont, via Solaroli 17, I-28100 Novara, Italy. grossini@med.unipmn.It
authors.forename: Elena
authors.initials: E
authors.lastname: Grossini
authors.forename: Claudio
authors.initials: C
authors.lastname: Molinari
authors.forename: Piero
authors.initials: P
authors.lastname: Pollesello
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bellomo
authors.forename: Guido
authors.initials: G
authors.lastname: Valente
authors.forename: David
authors.initials: D
authors.lastname: Mary
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vacca
authors.forename: Philippe
authors.initials: P
authors.lastname: Caimmi
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006835:Hydrazones / Q000494:pharmacology*; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008353:Mannitol / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011343:Procaine / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000077464:Simendan; D013552:Swine
chemical_list: D000975:Antioxidants; C039984:Bretschneider cardioplegic solution; D003652:Decanoic Acids; D006835:Hydrazones; D006880:Hydroxy Acids; D054086:KATP Channels; D011724:Pyridazines; D009569:Nitric Oxide; D000077464:Simendan; D008353:Mannitol; D011343:Procaine; C052853:5-hydroxydecanoic acid; D011189:Potassium Chloride; D019001:Nitric Oxide Synthase; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester