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. 2009 Sep 8;54(11):1024-32.
doi: 10.1016/j.jacc.2009.04.080.

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  1 , Alessandro Cataliotti, Brenda K Huntley, Fernando L Martin, Timothy M Olson, John C Burnett Jr
Affiliations

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 et al. J Am Coll Cardiol. .

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.

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Figures

Figure 1
Figure 1. Amino Acid Sequence of ANP and Mutant ANP
Amino acid sequence and structure of atrial natriuretic peptide (ANP) and mutant atrial natriuretic peptide (mANP).
Figure 2
Figure 2. In Vitro cGMP Generation in Response to ANP and Mutant ANP
In vitro 3′,5′cyclic guanosine monophosphate (cGMP) generation in cultured human cardiac fibroblasts in response to atrial natriuretic peptide (ANP) and mutant atrial natriuretic peptide (mANP) compared to controls (no treatment). Values are mean ± SEM. *P < 0.05 vs. control by unpaired t-tests.
Figure 3
Figure 3. Renal Excretory Response to High Dose ANP and Mutant ANP
Urine flow (UV) (3A), urine sodium excretion (UNaV) (3B), and distal tubular fractional sodium reabsorption (DFNaR) (3C) after infusion of high dose (33 pmol/kg/min) atrial natriuretic peptide (ANP) and mutant atrial natriuretic peptide (mANP) in normal dogs. BL represents baseline; Infusion, infusion of high dose (33 pmol/kg/min) of mANP or ANP; WO, washout (0–30 minutes post infusion); Rec 1, 30–60 minutes post infusion; Rec 2, 60–90 minutes post infusion; Rec 3, 90–120 minutes post infusion. Values are mean ± SEM. *P < 0.05 vs. baseline by 1-way ANOVA. †P < 0.05 for mANP vs. ANP at a specific time point as measured by 2-way ANOVA and Bonferroni posttests. P value shown in figure represents the main group effect between between ANP and mANP as measured by 2-way ANOVA.
Figure 4
Figure 4. Renin-Angiotension-Aldosterone Response to High Dose ANP and Mutant ANP
Measurement of the renin-angiotensin-aldosterone system after infusion of high dose (33 pmol/kg/min) atrial natriuretic peptide (ANP) and mutant atrial natriuretic peptide (mANP) in normal dogs. A, plasma renin activity; B, angiotensin II; C, aldosterone. BL represents baseline; Infusion, infusion of high dose (33 pmol/kg/min) of mANP or ANP; WO, washout (0–30 minutes post infusion); Rec 1, 30–60 minutes post infusion; Rec 2, 60–90 minutes post infusion; Rec 3, 90–120 minutes post infusion. Values are mean ± SEM. *P < 0.05 vs. baseline by 1-way ANOVA. P value shown in figure represents the main group effect between between ANP and mANP as measured by 2-way ANOVA.
Figure 5
Figure 5. Renal Excretory Response to Low Dose ANP and Mutant ANP
Urine flow (UV) (5A), urine sodium excretion (UNaV) (5B), and distal tubular fractional sodium reabsorption (DFNaR) (5C) after infusion of low dose (2 pmol/kg/min) atrial natriuretic peptide (ANP) and mutant atrial natriuretic peptide (mANP) in normal dogs. BL represents baseline; Infusion, infusion of low dose (2 pmol/kg/min) of mANP or ANP; WO, washout (0–30 minutes post infusion); Rec 1, 30–60 minutes post infusion; Rec 2, 60–90 minutes post infusion; Rec 3, 90–120 minutes post infusion. Values are mean ± SEM. *P < 0.05 vs. baseline by 1-way ANOVA. †P < 0.05 for mANP vs. ANP at a specific time point as measured by 2-way ANOVA and Bonferroni posttests. P value shown in figure represents the main group effect between between ANP and mANP as measured by 2-way ANOVA.
Figure 6
Figure 6. Urinary ANP Immunoreactivity Excretory Response to ANP and Mutant ANP
Urinary atrial natriuretic peptide immunoreactivity excretion (UANPV) after infusion of high dose (33 pmol/kg/min) (6A) and low dose (2 pmol/kg/min) (6B) of atrial natriuretic peptide (ANP) and mutant atrial natriuretic peptide (mANP). BL represents baseline; Infusion, infusion of low dose or high dose mANP or ANP; WO, washout (0–30 minutes post infusion); Rec 1, 30–60 minutes post infusion; Rec 2, 60–90 minutes post infusion; Rec 3, 90–120 minutes post infusion. Values are mean ± SEM. *P < 0.05 vs. baseline by 1-way ANOVA. †P < 0.05 for mANP vs. ANP at a specific time point as measured by 2-way ANOVA and Bonferroni posttests. P value shown in figure represents the main group effect between between ANP and mANP as measured by 2-way ANOVA.
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