Document Detail


A human atrial natriuretic peptide gene mutation reveals a novel peptide with enhanced blood pressure-lowering, renal-enhancing, and aldosterone-suppressing actions.
MedLine Citation:
PMID:  19729120     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP).
BACKGROUND: The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP((1-28)) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP.
METHODS: In vitro 3',5'-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs.
RESULTS: We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP.
CONCLUSIONS: These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.
Authors:
Paul M McKie; Alessandro Cataliotti; Brenda K Huntley; Fernando L Martin; Timothy M Olson; John C Burnett
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  54     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-04     Completed Date:  2009-09-29     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1024-32     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / genetics
Atrial Natriuretic Factor / genetics,  pharmacology*
Blood Pressure / drug effects*
Cell Culture Techniques
Cyclic GMP / metabolism
Dogs
Fibroblasts / drug effects*,  metabolism
Glomerular Filtration Rate / drug effects*
Humans
Mutant Proteins / pharmacology*
Mutation / genetics
Myocardium / metabolism,  pathology
Renin-Angiotensin System / drug effects*
Grant Support
ID/Acronym/Agency:
P01 HL076611/HL/NHLBI NIH HHS; P01 HL076611-05/HL/NHLBI NIH HHS; P01 HL76611/HL/NHLBI NIH HHS; R01 HL036634/HL/NHLBI NIH HHS; R01 HL036634-19A1/HL/NHLBI NIH HHS; R01 HL36634/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Mutant Proteins; 85637-73-6/Atrial Natriuretic Factor; H2D2X058MU/Cyclic GMP
Comments/Corrections
Comment In:
J Am Coll Cardiol. 2009 Sep 8;54(11):1033-4   [PMID:  19729121 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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