Nitric oxide synthase inhibition causes acute increases in glomerular permeability in vivo, dependent upon reactive oxygen species

Am J Physiol Renal Physiol. 2016 Nov 1;311(5):F984-F990. doi: 10.1152/ajprenal.00152.2016. Epub 2016 Sep 28.


There is increasing evidence that the permeability of the glomerular filtration barrier (GFB) is partly regulated by a balance between the bioavailability of nitric oxide (NO) and that of reactive oxygen species (ROS). It has been postulated that normal or moderately elevated NO levels protect the GFB from permeability increases, whereas ROS, through reducing the bioavailability of NO, have the opposite effect. We tested the tentative antagonism between NO and ROS on glomerular permeability in anaesthetized Wistar rats, in which the left ureter was cannulated for urine collection while simultaneously blood access was achieved. Rats were systemically infused with either l-NAME or l-NAME together with the superoxide scavenger Tempol, or together with l-arginine or the NO-donor DEA-NONOate, or the cGMP agonist 8-bromo-cGMP. To measure glomerular sieving coefficients (theta, θ) to Ficoll, rats were infused with FITC-Ficoll 70/400 (mol/radius 10-80 Å). Plasma and urine samples were analyzed by high-performance size-exclusion chromatography (HPSEC) for determination of θ for Ficoll repeatedly during up to 2 h. l-NAME increased θ for Ficoll70Å from 2.27 ± 1.30 × 10-5 to 8.46 ± 2.06 × 10-5 (n = 6, P < 0.001) in 15 min. Tempol abrogated these increases in glomerular permeability and an inhibition was also observed with l-arginine and with 8-bromo-cGMP. In conclusion, acute NO synthase inhibition in vivo by l-NAME caused rapid increases in glomerular permeability, which could be reversed by either an ROS antagonist or by activating the guanylyl cyclase-cGMP pathway. The data strongly suggest a protective effect of NO in maintaining normal glomerular permeability in vivo.

Keywords: Ficoll; cGMP; capillary permeability; glomerular filtration; glomerular sieving coefficient; soluble guanylyl cyclase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Glomerular Filtration Rate / drug effects
  • Hydrazines / pharmacology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism*
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Permeability / drug effects
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism*


  • Enzyme Inhibitors
  • Hydrazines
  • Reactive Oxygen Species
  • 8-bromocyclic GMP
  • 1,1-diethyl-2-hydroxy-2-nitrosohydrazine
  • Nitric Oxide Synthase
  • Cyclic GMP
  • NG-Nitroarginine Methyl Ester