Document Detail


Neuronal nitric oxide synthase supports Renin release during sodium restriction through inhibition of phosphodiesterase 3.
MedLine Citation:
PMID:  20651700     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Johan Sällström; Boye L Jensen; Ole Skøtt; Xiang Gao; A Erik G Persson
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-22
Journal Detail:
Title:  American journal of hypertension     Volume:  23     ISSN:  1941-7225     ISO Abbreviation:  Am. J. Hypertens.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-19     Completed Date:  2011-01-31     Revised Date:  2011-06-30    
Medline Journal Info:
Nlm Unique ID:  8803676     Medline TA:  Am J Hypertens     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1241-6     Citation Subset:  IM    
Affiliation:
Department of Medical Cell Biology, Uppsala University, Sweden. johan.sallstrom@mcb.uu.se
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / drug effects,  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,  enzymology
Male
Mice
Mice, Inbred Strains
Mice, Knockout
Milrinone / pharmacology
Nitric Oxide Synthase Type I / genetics*,  metabolism*
Phosphodiesterase 3 Inhibitors / pharmacology
Phosphodiesterase 5 Inhibitors / pharmacology
Purinones / pharmacology
Renal Circulation / drug effects,  physiology
Renin / metabolism*
Sodium Chloride, Dietary / pharmacology*
Chemical
Reg. No./Substance:
0/Phosphodiesterase 3 Inhibitors; 0/Phosphodiesterase 5 Inhibitors; 0/Purinones; 0/Sodium Chloride, Dietary; 37762-06-4/zaprinast; 60-92-4/Cyclic AMP; 7665-99-8/Cyclic GMP; 78415-72-2/Milrinone; EC 1.14.13.39/Nitric Oxide Synthase Type I; EC 1.14.13.39/Nos1 protein, mouse; EC 3.1.4.17/Cyclic Nucleotide Phosphodiesterases, Type 3; EC 3.1.4.35/Cyclic Nucleotide Phosphodiesterases, Type 5; EC 3.1.4.35/Pde5a protein, mouse; EC 3.4.23.15/Renin
Comments/Corrections
Comment In:
Am J Hypertens. 2010 Nov;23(11):1157   [PMID:  20956962 ]

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