Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs

Ischemia/reperfusion (I/R) injury is an important cause of acute renal failure due to 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 5 pigs each), I/R was induced by clamping-reopening of the left renal artery. During ischemia, in three groups of pigs, Levosimendan and the multi-organ preservation solution, Custodiol, alone or in combination with Levosimendan, were infused in the renal artery. In further two groups of animals, the administration of Levosimendan in combination with Custodiol was performed after intra-renal nitric oxide (NO) synthase blocker, Nω-nitro-L-arginine methyl ester, L-NAME, or the mitochondrial ATP-sensitive K+ channels (KATP) channels inhibitor, 5-hydroxydecanoate (5-HD). In the other animals, saline, L-NAME and 5-HD were administrated 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 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.