Potentiation of brain natriuretic peptides by SQ 28,603, an inhibitor of neutral endopeptidase 3.4.24.11, in monkeys and rats.
The depressor, natriuretic and cyclic GMP responses to several species of brain natriuretic peptide (BNP) were compared to atrial natriuretic peptide (ANP) 99-126 in conscious spontaneously hypertensive rats (SHR) and in conscious cynomolgus monkeys treated with vehicle or the selective neutral endopeptidase (NEP 3.4.24.11) inhibitor N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta- alanine (SQ 28,603). In the conscious SHR, the natriuretic and cyclic GMP responses to 3 nmol/kg i.v. rat BNP-32 greater than rat ANP 99-126 greater than pig BNP-26 and were significantly potentiated by 100 mumol/kg i.v. SQ 28,603. Human BNP-32 was inactive in the SHR treated with either vehicle or SQ 28,603. In contrast, 1 nmol/kg i.v. of human BNP-32 stimulated renal and depressor responses in the conscious monkeys that were greater than or equal to those elicited by human ANP 99-126, whereas 3 nmol/kg i.v. rat BNP-32 reduced mean arterial pressure without affecting renal function. Furthermore, SQ 28,603 (100 mumol/kg, i.v.) significantly enhanced the cumulative losses of sodium and cyclic GMP stimulated by each of these peptides. In conclusion, the renal and depressor activities of BNP are highly species specific and are significantly potentiated by an inhibitor of NEP 3.4.24.11 in conscious SHR and monkeys. Therefore, protection of endogenous BNP may contribute importantly to the activity of NEP 3.4.24.11 inhibitors in cardiorenal disorders such as hypertension and congestive heart failure.
Seymour
A A
AA
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
Asaad
M M
MM
Abboa-Offei
B E
BE
Rovnyak
P L
PL
Fennell
S
S
Rogers
W L
WL
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D020097:Natriuretic Peptide, Brain; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012964:Sodium / Q000652:urine; D013045:Species Specificity
D009419:Nerve Tissue Proteins; C065359:SQ 28603; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015260:Neprilysin; D000409:Alanine