Abstract
Neutral endopeptidase 24.11 (NEP) inhibitors are known to have vascular, diuretic, and natriuretic effects that may be helpful in the treatment of congestive heart failure (CHF). Most NEP inhibitors may act principally through intrarenal mechanisms, which are not completely understood. The purpose of this study was to determine the principal renal effects of the NEP inhibitor ecadotril in dogs with progressive CHF induced by rapid ventricular pacing. Renal function was measured before, during, and after acute i.v. infusion of normal saline in a total of six dogs during normal cardiac function, early left ventricular dysfunction, and overt CHF. During overt CHF, each dog was treated with either ecadotril or placebo orally for 1 week. Parameters measured included glomerular filtration rate, renal blood flow, urine output, sodium clearance, sodium fractional excretion, and proximal and distal sodium reabsorption. Ecadotril treatment resulted in increased urine output, sodium clearance, and renal sodium excretion relative to placebo-treated controls. The principal intrarenal effect of ecadotril was decreased distal renal tubular sodium reabsorption. Both glomerular filtration rate and renal blood flow declined during overt CHF and were unaffected by ecadotril treatment. The results of this study are consistent with the principal action of ecadotril occurring by way of intrarenal events as opposed to changes in renal hemodynamics. The principal effect of ecadotril on distal tubular sodium reabsorption suggests that inhibition of NEP activity in the proximal renal tubules may allow increased binding of filtered atrial natriuretic peptide to natriuretic peptide receptor sites in the distal renal tubules and collecting ducts.
Footnotes
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Send reprint requests to: Philip F. Solter, University of Illinois, College of Veterinary Medicine, 1008 W. Hazelwood Dr., Urbana, IL 61802.
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↵1 This study was supported by Bayer AG, Monheim, Germany.
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↵2 Current address: University of California-Davis, Veterinary Medical Teaching Hospital, Davis, CA, 95616-8737.
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↵3 Current address: Bayer AG, GB-TG/Pharmakologie, Monheim 6700, 51368 Leverkusen, Germany.
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↵4 Steinke W and Schwarz T. [14-C]BAY y 7432: Distribution of the radioactivity in rats after single oral and i.v. administration (whole body autoradiography). PH-report 23165, April 11, 1994, Bayer AG.
- Abbreviations:
- NEP
- Neutral endopeptidase 24.11
- CHF
- congestive heart failure
- ANP
- atrial natriuretic peptide
- NPR-A
- natriuretic peptide receptor-A
- bpm
- beats per minute
- PAH
- para-aminohippurate
- VE
- volume expansion
- PCV
- packed cell volume
- GFR
- glomerular filtration rate
- RBF
- renal blood flow
- Received November 17, 1999.
- Accepted February 7, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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