Hypoxanthine plus xanthine oxidase causes profound natriuresis without affecting renal blood flow autoregulation

Abstract

Enhanced superoxide (O2-.) production by xanthine oxidase in ischemia/reperfusion has been implicated in structural damage. The reperfusion phase is accompanied by decreased tubular sodium reabsorption, which has been partly attributed to enhanced action of O2-. In the present study we assessed whether intrarenal increases of O2-. accomplished by concomitant intrarenal hypoxanthine and intravenous xanthine oxidase (HX/XO) infusion would decrease or increase sodium excretion, and whether HX/XO infusion could be responsible for the diminished efficacy of renal blood flow (RBF) autoregulation in ischemia/reperfusion. In the first group of Sprague-Dawley rats, renal sodium handling was measured before and during O2-. infusion. In the second group, renal hemodynamics and RBF autoregulation were assessed. Intrarenal O2-. infusion dramatically increased urine flow from 14.5 +/- 2.0 microL/min to 46.3 +/- 4.4 microL/min, urinary excretion of sodium (UNaV) from 1.7 +/- 0.4 micromol/min to 8.6 +/- 0.9 micromol/min, and fractional excretion of sodium FENa from 1.2 +/- 0.4% to 7.6 +/- 1.2%. Urinary excretion of thiobarbituric acid reactive substances (TBARS), a measure of lipid peroxidation, increased during HX/XO infusion. These changes were completely reversible. Glomerular filtration rate (GFR) decreased from 1.12 +/- 0.08 during baseline to 0.79 +/- 0.06 during HX/XO (P < 0.05) and tended to increase toward baseline during recovery (0.84 +/- 0.06 mL/min/g kidney weight). HX/XO did not significantly affect mean arterial pressure (MAP). HX/XO decreased RBF in the second group from 8.4 +/- 0.6 mL/min/g kidney weight to 7.4 +/- 0.5 mL/min/g kidney weight (P < 0.05) and renal vascular resistance (RVR) slightly increased from 13.8 +/- 0.9 units under baseline conditions to 15.1 +/- 1.1 units during HX/XO infusion (P < 0.05). HX/XO did not significantly affect RBF autoregulation. Proteinuria and glucosuria were absent and light microscopy revealed no renal morphologic changes. Intrarenal O2-. infusion (1) dramatically increased sodium and volume excretion and (2) did not affect autoregulation of RBF. Thus, superoxide can markedly affect glomerulotubular balance by diverging actions on renal hemodynamics and reabsorptive function and could mediate the functional tubular consequences of ischemia/reperfusion.