ROLE OF INCREASED OXYGEN-FREE RADICAL ACTIVITY IN THE PATHOGENESIS OFUREMIC 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 ox ide (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 contri bute to CRF hypertension. Four weeks after 5/6 nephrectomy rats were t reated for two weeks with either lazaroid, a potent antioxidant and li pid peroxidation inhibitor (CRF-LZ group), or vehicle alone (CRF group ) by daily gastric gavage. The control group was sham operated and pla cebo treated. The CRF group exhibited significant increases in BP and plasma lipid peroxidation product, malondialdehyde (MDA), indicating e nhanced OFR activity. This was accompanied by decreased urinary nitrat e/nitrite (NOx) excretion suggesting depressed NO production. LZ thera py normalized plasma MDA and significantly ameliorated CRF-induced hyp ertension 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, dimethyl thiourea (DMTU), significantly lowered BP and raised urinary NOx excre tion. However, no discernible effects were found with either superoxid e dismutase or catalase (superoxide and H2O2 quenchers). The results s uggest that increased OFR activity is, in part, responsible for CRF-as sociated HTN. The study further points to hydroxyl radicals as the maj or source of OFR in CRF animals. If substantiated in humans, antioxida nt therapy becomes a logical adjunct in the management of CRF.