Hormones – Cytokines – Signalling

Kidney International (2005) 67, 1723–1730; doi:10.1111/j.1523-1755.2005.00269.x

Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure

FERNANDO L MARTIN, TRACY L STEVENS, ALESSANDRO CATALIOTTI, JOHN A SCHIRGER, DANIEL D BORGESON, MARGARET M REDFIELD, ANDREAS LUCHNER and JOHNC BURNETT JR

Cardiorenal Research Laboratory, the Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota

Correspondence: Linda Combs, Fernando L. Martin,M.D., Mayo Clinic, 200 First Street SW, Guggenheim 9–01, Rochester, MN 55905. E-mail: combs.linda@mayo.eduMayo Clinic and Foundation, 200 First Street SW, Guggenheim 9–01, Rochester, MN 55905. E-mail: martin.fernando@mayo.edu

Received 20 October 2004; Revised 5 November 2004; Accepted 18 November 2004.

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Abstract

Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure.

Background

 

Neutral endopeptidase (NEP) degrades atrial natriuretic peptide (ANP) that via cyclic guanosine monophosphate (cGMP) is natriuretic and aldosterone-inhibiting. We hypothesized that chronic oral NEP inhibition (NEPI), initiated in early experimental congestive heart failure (CHF), would delay onset of decreases in sodium excretion during the progression of CHF and, in the severe phase, suppress aldosterone activation and reduce the magnitude of sodium retention. We also hypothesized that chronic NEPI during progressive CHF (PCHF) would improve the natriuretic response to acute volume expansion.

Methods

 

In a novel canine model that progresses over 38 days from early to moderate and finally severe CHF, we defined the actions of chronic NEPI (candoxatril, 10 mg/kg, orally, twice a day) upon cardiorenal and neurohumoral function as well as the clinical well being of treated and untreated dogs in CHF.

Results

 

From baseline through the moderate phase of CHF, NEPI maintained sodium excretion. In contrast, in moderate CHF, sodium excretion was reduced compared to the early phase in the controls. In severe CHF, sodium excretion was higher with NEPI compared to control. Chronic NEPI also resulted in lower plasma aldosterone as compared to controls. In severe CHF, the natriuretic response to acute saline volume expansion was enhanced with oral NEPI as compared to control.

Conclusion

 

This study supports the conclusion that chronic oral NEPI delays the onset of reduction in sodium excretion during the transition from early to severe CHF in this model of PCHF. This therapeutic strategy also improved the natriuretic response to acute volume expansion in severe CHF while enhancing ANP and suppressing aldosterone activation. Thus, these studies demonstrated a selective renal and adrenal action of chronic NEPI in heart failure indicating a therapeutic potential.

Keywords:

heart failure, atrial natriuretic factor, kidney, aldosterone

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