Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure

Abstract

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA₂ mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23 ± 3%; p < 0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60 ± 20%; p < 0.05) but reduced AngII vasoconstriction (51 ± 11%; p < 0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB₂ levels in ARF. Candoxatril reduced plasma AngII by 34 ± 4% (p < 0.05) in ARF which was ∼3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na⁺ and creatinine excretion in ARF by 73 ± 9% and 33 ± 2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.

Keywords:

• acute renal failure
• glycerol
• candoxatril
• endothelin-1
• vasoconstriction

Acknowledgments

This study was supported by National Institutes of Health Grant HL03674.