The effect of dilazep on puromycin-induced rat renal mitochondrial dysfunction.
The effect of tetrahydro-1 H-1,4 (5H)-dipropanol bis(3,4,5-trimethoxybenzoate)hydrochloride monohydrate (dilazep, Comelian) on puromycin-induced rat renal damage was investigated. In vivo study: Rats were divided into 3 groups, the control group; untreated, the puromycin group; puromycin (150 mg/kg) was injected intraperitoneally once, the dilazep + puromycin group; puromycin (150 mg/kg) was injected 1 h after intraperitoneal dilazep injection (2 mg/kg), and dilazep (2 mg/kg) was injected every 12 h until the end of the experiment. In each group, 84 h after puromycin injection, kidneys were isolated and renal mitochondria were prepared. The endogenous phospholipase activity in kidney homogenate was determined by high performance liquid chromatography. The activities of three segments (NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome c oxidase) of the electron-transport chain in mitochondria were measured enzymatically. In the puromycin group, phospholipase activity was increased and activities of all of three segments of the electron-transport chain were decreased. In the dilazep + puromycin group, premedication with dilazep prevented activation of phospholipase and maintained mitochondrial electron-transport activity. In vitro study: Mitochondria prepared from intact rat kidney were incubated with phospholipase C. Activities of the mitochondrial electron-transport chain were deteriorated by phospholipase C. These results indicated that activation of endogenous phospholipase, which digests membrane phospholipids, essential components in maintaining mitochondrial electron-transport activity, is responsible for the puromycin-induced renal damage. Premedication with dilazep prevented the damage by inhibition of the activation of phospholipase.
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D004109:Dilazep / Q000494:pharmacology*; D004579:Electron Transport; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D011691:Puromycin / Q000633:toxicity*; D051381:Rats; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism
D001381:Azepines; D011691:Puromycin; D013384:Succinate Cytochrome c Oxidoreductase; D009245:NADH Dehydrogenase; D010740:Phospholipases; D004109:Dilazep