Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

J Am Heart Assoc. 2018 Aug 7;7(15):e009501. doi: 10.1161/JAHA.118.009501.


Background Renal hypoxia, implicated as crucial factor in onset and progression of chronic kidney disease, may be attributed to reduced nitric oxide because nitric oxide dilates vasculature and inhibits mitochondrial oxygen consumption. We hypothesized that chronic nitric oxide synthase inhibition would induce renal hypoxia. Methods and Results Oxygen-sensitive electrodes, attached to telemeters, were implanted in either renal cortex (n=6) or medulla (n=7) in rats. After recovery and stabilization, baseline oxygenation ( pO 2) was recorded for 1 week. To inhibit nitric oxide synthase, N-ω-nitro-l-arginine (L-NNA; 40 mg/kg/day) was administered via drinking water for 2 weeks. A separate group (n=8), instrumented with blood pressure telemeters, followed the same protocol. L-NNA rapidly induced hypertension (165±6 versus 108±3 mm Hg; P<0.001) and proteinuria (79±12 versus 17±2 mg/day; P<0.001). Cortical pO 2, after initially dipping, returned to baseline and then increased. Medullary pO 2 decreased progressively (up to -19±6% versus baseline; P<0.05). After 14 days of L-NNA, amplitude of diurnal medullary pO 2 was decreased (3.7 [2.2-5.3] versus 7.9 [7.5-8.4]; P<0.01), whereas amplitudes of blood pressure and cortical pO 2 were unaltered. Terminal glomerular filtration rate (1374±74 versus 2098±122 μL/min), renal blood flow (5014±336 versus 9966±905 μL/min), and sodium reabsorption efficiency (13.0±0.8 versus 22.8±1.7 μmol/μmol) decreased (all P<0.001). Conclusions For the first time, we show temporal development of renal cortical and medullary oxygenation during chronic nitric oxide synthase inhibition in unrestrained conscious rats. Whereas cortical pO 2 shows transient changes, medullary pO 2 decreased progressively. Chronic L-NNA leads to decreased renal perfusion and sodium reabsorption efficiency, resulting in progressive medullary hypoxia, suggesting that juxtamedullary nephrons are potentially vulnerable to prolonged nitric oxide depletion.

Keywords: hypoxia; nitric oxide synthase; oxygen consumption; renal oxygenation; telemetry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Blood Pressure / physiology
  • Enzyme Inhibitors / pharmacology*
  • Glomerular Filtration Rate / drug effects
  • Glomerular Filtration Rate / physiology
  • Hypertension
  • Hypoxia*
  • Kidney Cortex / drug effects*
  • Kidney Cortex / metabolism
  • Kidney Medulla / drug effects*
  • Kidney Medulla / metabolism
  • Male
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitroarginine / pharmacology*
  • Oxygen / metabolism*
  • Proteinuria
  • Rats
  • Renal Circulation / drug effects
  • Renal Circulation / physiology
  • Sodium / metabolism


  • Enzyme Inhibitors
  • Nitroarginine
  • Sodium
  • Nitric Oxide Synthase
  • Oxygen