Effects of neutral endopeptidase inhibition on the clearance of exogenously administered endothelin in Sprague-Dawley rats.
The effects of the selective neutral endopeptidase (EC 3.4.24.11, NEP) inhibitor SQ 28,603 on endogenous plasma endothelin (ET) concentration and on the clearance from the circulation of exogenously administered synthetic human ET-1 were examined in Sprague-Dawley rats. Inhibition of NEP by SQ 28,603 (100 mumol/kg intravenously, i.v.) affected neither basal levels of plasma ET nor the circulatory clearance of an i.v. administered bolus dose (3 nmol/kg) of ET-1. ET-1 produced marked, statistically significant increases in plasma atrial natriuretic peptide (ANP) and cyclic GMP concentrations. SQ 28,603 markedly augmented the duration of the increases in plasma concentrations of ANP and cyclic GMP induced by exogenous ET-1. SQ 28,603 alone produced modest but statistically significant increases in plasma ANP and cyclic GMP concentrations that lasted for at least 30 min. These results clearly demonstrate that NEP does not contribute to the in vivo clearance of ET and support the hypothesis that NEP plays an important role in clearance of ANP from the circulation.
Asaad
M M
MM
Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
Dorso
C R
CR
Moreland
S M
SM
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006152:Cyclic GMP / Q000097:blood; D016232:Endothelins / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008657:Metabolic Clearance Rate; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016232:Endothelins; C065359:SQ 28603; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D006152:Cyclic GMP; D000409:Alanine