Renal effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine, a novel selective inhibitor of neutral endopeptidase 24.11 (Neprilysin): comparison with SQ 28,603.
The effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine (MA-LF) on the activity of neutral endopeptidase and on renal hemodynamics and excretory function were investigated in experiments in vitro and in vivo. In vitro studies showed that the compound effectively inhibited purified bovine kidney neutral endopeptidase (Ki = 0.012 microM), while having slight influence on the activity of angiotensin I converting enzyme (Ki = 0.14 microM). In experiments on normal anesthetized rats (thiobutabarbital sodium salt, 100 mg/kg), IV administration of MA-LF (20 and 60 mg/kg) produced a dose-dependent increase in absolute rate and fractional excretion of sodium (+324% and +299%, respectively) and urinary flow rate (+261%), but did not change renal and systemic hemodynamics. Renal excretory effects of the new compound were comparable to those of the selective neutral endopeptidase inhibitor SQ 28,603. These results demonstrate that MA-LF is a potent neutral endopeptidase inhibitor with prominent natriuretic and diuretic properties.
Gurbanov
K
K
Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Shuranyi
E
E
Kaballa
A
A
Fudim
E
E
Blumberg
S
S
Winaver
J
J
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014563:Urodynamics / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D004151:Dipeptides; D004791:Enzyme Inhibitors; C065359:SQ 28603; C038771:2-mercaptoacetyl-phenylalanylleucine; D012964:Sodium; D015260:Neprilysin; D000409:Alanine