The Mitochondrial K-ATP Channel Opener, Diazoxide, Prevents Ischemia-Reperfusion Injury in the Rabbit Spinal Cord

Abstract

Paraplegia resulting from ischemia is a catastrophic complication of thoracoabdominal aortic surgery. The current study was designed to investigate the effects of diazoxide (DZ) on mitochondrial structure, neurological function, DNA damage-repair, and apoptosis in spinal cord ischemia-reperfusion injury. Rabbits were subjected to 30 minutes of spinal cord ischemia and reperfusion (1 hour) with or without diazoxide (n = 6 in each group) by clamping and releasing the infrarenal aorta. The neurological functional score was significantly improved in the DZ-treated ischemia-reperfusion injury group. Electron microscopic studies demonstrated that mitochondrial damage in the spinal cord after injury was significantly reduced by DZ. Mitochondrial superoxide and hydrogen peroxide levels were also markedly decreased in the DZ-treated injury group compared with the untreated group. DZ decreased levels of the oxidative DNA damage product 8-oxoG and increased levels of the DNA repair enzyme OGG-1. Furthermore, DZ inhibited apoptosis via caspase-dependent and -independent pathways. These studies indicate for the first time that the mitochondrial K-ATP channel opener diazoxide improves neurological function after spinal cord ischemia and reperfusion by diminishing levels of reactive oxygen species, decreasing DNA oxidative damage, and inhibiting caspase-dependent and -independent apoptotic pathways while preserving mitochondrial structure.

Amelioration of oxidative mitochondrial DNA damage and deletion after renal ischemic injury by the KATP channel opener diazoxide

“…Interestingly, kidneys treated with SOD fared much better in the long run (22). It was somewhat surprising that agents opening the ATP-sensitive K ϩ (K ATP ) channel, which has been found to be effective in ameliorating cardiac and neural I/R injury (7,9,31,34,39), have been reported to be ineffective in kidney I/R injury and, possibly, injurious (8,33,36). Glibenclamide, which closes K ATP channels, was reported to be effective in reducing renal I/R injury (33).…”

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

“…Pretreatment with verapamil, a voltage-dependent calcium channel blocker, prior to animal ischemia-reperfusion resulted in significant inhibition of Ca +2 accumulation in hepatocytes [134]. Mitochondrial ATD-sensitive potassium channels (mitoKATP) and mPTP differences altered mitochondrial Ca +2 balance, induced mitoKATP opening to mitochondrial membrane partial depolarization and inhibition of mPTP can reduce Ca +2 influx, thereby reducing calcium overload [135]. A Na + -Ca +2 exchange inhibitor, KB-R7943, inhibited apoptosis, activated K + -ATP channels, promoted K + and Ca +2 exchange, and inhibited calcium overload [136].…”

The effect of mitochondrial ATP-sensitive potassium channels on apoptosis of chick embryo cecal cells by Eimeria tenella

“…Diazoxide specifically opens mitoKATP channels (Gribble et al, 1997;Ichinose et al, 2003;Roseborough et al, 2006) and has been found to limit ischemia-reperfusion injury and apoptosis in a number of in vivo and in vitro models (Liu et al, 2002;Teshima et al, 2003). Although the concentrations of diazoxide required to affect activity of mitoKATP channels in cardioprotection are lower than those required to inhibit succinate dehydrogenase (SDH) (Kowaltowski et al, 2001), Wojtovich et al have suggested that SDH has a potential role in either mitoKATP channel composition or (Ardehali et al, 2004).…”