Intrarenal effects of ecadotril during acute volume expansion in dogs withcongestive heart failure

Neutral endopeptidase 24.11 (NEP) inhibitors are known to have vascular, di uretic, and natriuretic effects that may be helpful in the treatment of con gestive heart failure (CHF). Most NEP inhibitors may act principally throug h intrarenal mechanisms, which are not completely understood. The purpose o f this study was to determine the principal renal effects of the NEP inhibi tor ecadotril in dogs with progressive CHF induced by rapid ventricular pac ing. Renal function was measured before, during, and after acute i.v. infus ion 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. Paramet ers measured included glomerular filtration rate, renal blood flow, urine o utput, sodium clearance, sodium fractional excretion, and proximal and dist al sodium reabsorption. Ecadotril treatment resulted in increased urine out put, sodium clearance, and renal sodium excretion relative to placebo-treat ed controls. The principal intrarenal effect of ecadotril was decreased dis tal 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 act ion of ecadotril occurring by way of intrarenal events as opposed to change s in renal hemodynamics. The principal effect of ecadotril on distal tubula r sodium reabsorption suggests that inhibition of NEP activity in the proxi mal renal tubules may allow increased binding of filtered atrial natriureti c peptide to natriuretic peptide receptor sites in the distal renal tubules and collecting ducts.