Neuronal nitric oxide synthase supports Renin release during sodium restriction through inhibition of phosphodiesterase 3

Am J Hypertens. 2010 Nov;23(11):1241-6. doi: 10.1038/ajh.2010.153. Epub 2010 Jul 22.


Background: Mice with targeted deletion of neuronal nitric oxide (NO) synthase (nNOS⁻(/)⁻) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa (MD), and in the present study, it was tested whether nNOS supports renin release by cyclic guanosine monophosphate (cGMP)-mediated inhibition of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase 3 (PDE3) in juxtaglomerular (JG) cells.

Methods: The experiments were performed in conscious nNOS⁻(/)⁻ and wild types after 10 days on a low-sodium diet by acute treatment with the PDE3-inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and para-amino hippuric acid (PAH) clearances, respectively.

Results: The basal PRC was reduced in nNOS⁻(/)⁻ compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS⁻(/)⁻, resulting in normalized renin levels, whereas PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone.

Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the JG cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Female
  • Juxtaglomerular Apparatus / physiology
  • Kidney Cortex / drug effects
  • Kidney Cortex / enzymology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Milrinone / pharmacology
  • Nitric Oxide Synthase Type I / genetics*
  • Nitric Oxide Synthase Type I / metabolism*
  • Phosphodiesterase 3 Inhibitors / pharmacology
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Purinones / pharmacology
  • Renal Circulation / drug effects
  • Renal Circulation / physiology
  • Renin / metabolism*
  • Sodium Chloride, Dietary / pharmacology*


  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase 5 Inhibitors
  • Purinones
  • Sodium Chloride, Dietary
  • Cyclic AMP
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, mouse
  • Renin
  • zaprinast
  • Cyclic GMP
  • Milrinone