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A human atrial natriuretic peptide gene mutation reveals a novel peptide with enhanced blood pressure-lowering, renal-enhancing, and aldosterone-suppressing actions.

Abstract：

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.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

McKie PM,Cataliotti A,Huntley BK,Martin FL,Olson TM,Burnett JC Jr

doi

10.1016/j.jacc.2009.04.080

subject

Has Abstract

pub_date

2009-09-08 00:00:00

pages

1024-32

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(09)02062-2

journal_volume

pub_type

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A human atrial natriuretic peptide gene mutation reveals a novel peptide with enhanced blood pressure-lowering, renal-enhancing, and aldosterone-suppressing actions.