Potentiation of the Depressor Responses to Atrial Natriuretic Peptides in Conscious SHR by an Inhibitor of Neutral Endopeptidase

Abstract

In previous studies, neutral endopeptidase (NEP) hydrolyzed the Cys105-Phe106 bond of atrial natriuretic peptides (ANP) in vitro. Three such ring-opened peptides derived from ANP 99-126, 103-126, and 103-123 were inactive in conscious rats. In conscious spontaneously hypertensive rats (SHR) in the present study, 100 .mu.mol/kg, intravenously (i.v.) of the NEP inhibitor, SQ 29,072 (7-[[2-(mercaptomethyl)-1-oxo-3-phenyl-propyl]amino]heptanoic acid), significantly incresed the area over the curve (AOC) of the depressor response to 3 nmol/kg of ANP 103-126 from 165 .+-. 36 to 792 .+-. 350, 1,515 .+-. 374, and 828 .+-. 164 mm Hg .cntdot. min at 15, 30, and 60 min after inhibitor treatment. Thirty minutes after 3, 10, 30, and 100 .mu.mol/kg of SQ 29,072, the AOC of 3 nmol/kg of ANP 99-126 increased from 175 .+-. 59 mm Hg .cntdot. min in vehicle-treated rats to 296 .+-. 100, 318 .+-.U 34,632 .+-. 194 (p < 0.05) and 656 .+-. 151 (p < 0.05) mm Hg .cntdot. min. Furthermore, 100 .mu.mol/kg of SQ 29,072 potentiated the AOC of human ANP 99-126 and 105-126 and rat ANP 99-126, 103-126, and 103-123, suggesting that the exocyclic N-terminal residues and the C-terminal tripeptide did not influence ANP potentiation by SQ 29,072. In contrast, inhibitors of aminopeptidase, angiotensin-converting enzyme (ACE), and serine protease and an arginine vasopressin (AVP) antagonist did not substantially affect the AOC of 3 nmol/kg ANP 99-126. Finally SQ 29,072 did not alter the activities of bradykinin, AVP, or angiotensin I or II. In conclusion, NEP may inactivate ANP in vivo by cleavage of susceptible bonds within the ANP ring.