TY - JOUR T1 - Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 376 LP - 388 DO - 10.1124/jpet.112.193961 VL - 342 IS - 2 AU - Elena Grossini AU - Claudio Molinari AU - Piero Pollesello AU - Giorgio Bellomo AU - Guido Valente AU - David Mary AU - Giovanni Vacca AU - Philippe Caimmi Y1 - 2012/08/01 UR - http://jpet.aspetjournals.org/content/342/2/376.abstract N2 - 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. ER -