Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension.
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.
Vaziri
N D
ND
Department of Medicine, University of California, Irvine, USA.
Oveisi
F
F
Ding
Y
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009573:Nitrites / Q000097:blood / Q000652:urine; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000502:physiology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014511:Uremia / Q000209:etiology*
D000975:Antioxidants; D016166:Free Radical Scavengers; D009573:Nitrites; D011281:Pregnatrienes; D017382:Reactive Oxygen Species; C074965:U 74389F; D008315:Malondialdehyde; C038983:1,3-dimethylthiourea; D013482:Superoxide Dismutase; D013890:Thiourea