Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure.
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 approximately 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.
Newaz
Mohammad
M
College of Pharmacy, Chicago State University, Chicago, IL 60628, USA. mnewaz@csu.edu
Yousefipour
Zivar
Z
Oyekan
Adebayo
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology*; D000284:Administration, Oral; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009566:Nitrates / Q000652:urine; D011422:Propionates / Q000494:pharmacology; D011507:Proteinuria; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D007189:Indans; D009566:Nitrates; D011422:Propionates; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C062766:candoxatril; D003404:Creatinine; D015260:Neprilysin