Published Online
on January 22, 2002

A more recent version of this article appeared on February 26, 2002

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Submitted on October 15, 2001
Revised on December 6, 2001
Accepted on December 21, 2001

Maximizing the Natriuretic Peptide System in Experimental Heart Failure. Subcutaneous Brain Natriuretic Peptide and Acute Vasopeptidase Inhibition

Horng H. Chen MB, BCh^*, John G. Lainchbury MD, Gail J. Harty VMT, and John C. Burnett Jr MD

From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, Minn.

^* To whom correspondence should be addressed. E-mail: chen.horng{at}mayo.edu.

Background—A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF.

Methods and Results—We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 µmol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 µg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 µg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone.

Conclusions—This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.

Key words: natriuretic peptides • heart failure • pacing

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