A human atrial natriuretic peptide gene mutation reveals a novel peptide with enhanced blood pressure-lowering, renal-enhancing, and aldosterone-suppressing actions.
OBJECTIVE
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.
McKie
Paul M
PM
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. mckie.paul@mayo.edu
Cataliotti
Alessandro
A
Huntley
Brenda K
BK
Martin
Fernando L
FL
Olson
Timothy M
TM
Burnett
John C
JC
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D018929:Cell Culture Techniques; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D050505:Mutant Proteins / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects*
D050505:Mutant Proteins; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP