Potentiation of the depressor responses to atrial natriuretic peptides in conscious SHR by an inhibitor of neutral endopeptidase.
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 mumol/kg, intravenously (i.v.) of the NEP inhibitor, SQ 29,072 (7-[[2-(mercaptomethyl)-1-oxo-3-phenyl-propyl]amino]heptanoic acid), significantly increased 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.min at 15, 30, and 60 min after inhibitor treatment. Thirty minutes after 3, 10, 30, and 100 mumol/kg of SQ 29,072, the AOC of 3 nmol/kg of ANP 99-126 increased from 175 +/- 59 mm Hg.min in vehicle-treated rats to 296 +/- 100, 318 +/- 34, 632 +/- 194 (p less than 0.05) and 656 +/- 151 (p less than 0.05) mm Hg.min. Furthermore, 100 mumol/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.
Seymour
A A
AA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08540.
Swerdel
J N
JN
Fennell
S A
SA
Druckman
S P
SP
Neubeck
R
R
Delaney
N G
NG
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013997:Time Factors
D000596:Amino Acids; D010446:Peptide Fragments; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; C060193:SQ 29072; D009320:Atrial Natriuretic Factor; C062522:atrial natriuretic factor prohormone (103-123)