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PRE-CLINICAL RESEARCH

A Human Atrial Natriuretic Peptide Gene Mutation Reveals a Novel Peptide With Enhanced Blood Pressure-Lowering, Renal-Enhancing, and Aldosterone-Suppressing Actions

Paul M. McKie, MD^_*,_*, Alessandro Cataliotti, MD, PhD^_*, Brenda K. Huntley, BS^_*, Fernando L. Martin, MD^_*, Timothy M. Olson, MD and John C. Burnett, Jr, MD^_*

^_* Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota
Cardiovascular Genetics Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota

Manuscript received January 20, 2009; revised manuscript received March 31, 2009, accepted April 20, 2009.

^_* Reprint requests and correspondence: Dr. Paul M. McKie, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905 (Email: mckie.paul{at}mayo.edu).

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.

Key Words: natriuretic peptide • kidney • heart failure • blood pressure • aldosterone • angiotensin

Abbreviations and Acronyms   AA = amino acid   ANP = atrial natriuretic peptide   cGMP = 3',5'-cyclic guanosine monophosphate   CLLi = lithium clearance   DFRNa = distal fractional reabsorption of sodium   DNP = Dendroaspis natriuretic peptide   GFR = glomerular filtration rate   mANP = mutant atrial natriuretic peptide   MAP = mean arterial blood pressure   NEP = neutral endopeptidase   NPR = natriuretic peptide receptor   PCWP = pulmonary capillary wedge pressure   PFRNa = proximal fractional reabsorption of sodium   RAAS = renin-angiotensin-aldosterone system   RBF = renal blood flow

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