1-3-dimethylthiourea and Kidney-Failure--Chronic

Earlier studies have demonstrated increased oxygen free radical (OFR) activity, diminished antioxidant capacity and reduced OFR-inactivating enzymes in chronic renal failure (CRF). Via inactivation of nitric oxide (NO), oxidation of arachidonic acid and a direct vasoconstrictive action, OFR can potentially raise blood pressure (BP). This study was designed to test the hypothesis that increased OFR activity may contribute to CRF hypertension. Four weeks after 5/6 nephrectomy rats were treated for two weeks with either lazaroid, a potent antioxidant and lipid peroxidation inhibitor (CRF-LZ group), or vehicle alone (CRF group) by daily gastric gavage. The control group was sham operated and placebo treated. The CRF group exhibited significant increases in BP and plasma lipid peroxidation product, malondialdehyde (MDA), indicating enhanced OFR activity. This was accompanied by decreased urinary nitrate/nitrite (NOx) excretion suggesting depressed NO production. LZ therapy normalized plasma MDA and significantly ameliorated CRF-induced hypertension. Both MDA and blood pressure (BP) rose to values seen in the untreated CRF group within two weeks after termination of LZ therapy. Intravenous administration of the hydroxyl radical scavenger, dimethylthiourea (DMTU), significantly lowered BP and raised urinary NOx excretion. However, no discernible effects were found with either superoxide dismutase or catalase (superoxide and H2O2 quenchers). The results suggest that increased OFR activity is, in part, responsible for CRF-associated HTN. The study further points to hydroxyl radicals as the major source of OFR in CRF animals. If substantiated in humans, antioxidant therapy becomes a logical adjunct in the management of CRF.

Topics: Animals; Antioxidants; Blood Pressure; Free Radical Scavengers; Hypertension; Kidney Failure, Chronic; Male; Malondialdehyde; Nitrites; Pregnatrienes; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Thiourea; Uremia

The synergistic mechanism by which endotoxin enhances the nephrotoxic potential of gentamicin is unknown. In this study, we attempted to shed light on this mechanism by injecting rats with endotoxin plus gentamicin. Renal injury was assessed by measuring creatinine, inulin and PAH clearance, NADH levels and electrolyte reabsorption, for 24 hr following this injection. Gentamicin alone (20 mg/100 g) induced no renal injury, while endotoxin without gentamicin (0.075 mg/100 g) induced mild injury. However, endotoxin plus gentamicin resulted in acute renal failure. In an attempt to halt the progressive renal dysfunction, the antioxidants NAO (5 mg/100 g), Vitamin E (0.2 mg/100 g per day) and dimethylthiourea (DMTU-50 mg/100 g) were administered, or early endotoxin tolerance was induced before injecting the rats with endotoxin plus gentamicin. The reduction in renal function was markedly slower in rats administered with antioxidants compared with untreated rats. Similar results were obtained with endotoxin tolerance. These data suggest that NAO, vitamin E, DMTU and endotoxin tolerance are potentially beneficial in arresting progressive renal damage associated with endotoxin plus gentamicin.

Topics: Animals; Antioxidants; Dose-Response Relationship, Drug; Endotoxins; Free Radical Scavengers; Gentamicins; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Lipid Peroxidation; Male; Plant Extracts; Rats; Thiourea; Vitamin E