SCH 39370, a neutral metalloendopeptidase inhibitor, potentiates biological responses to atrial natriuretic factor and lowers blood pressure in desoxycorticosterone acetate-sodium hypertensive rats.
SCH 39370 (N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl]-(S)-isoserin e) is a potent and specific inhibitor of neutral metalloendopeptidase (NEP) from rabbit kidney (IC50 = 11.2 +/- 1.9 nM) and is devoid of angiotensin-converting enzyme inhibitory activity at 1 microM. We evaluated the effect of NEP inhibition with SCH 39370 on the inactivation of atrial natriuretic factor (ANF) and on cardiovascular function in rats. SCH 39370 effectively prevented in vitro degradation of ANF (99-126) by a purified rabbit kidney NEP. SCH 39370 (30 mg/kg s.c) significantly delayed the disappearance of immunoreactive (ir) ANF from plasma in rats after an i.v. infusion of ANF (1 microgram/kg/min for 30 min): the plasma ir ANF level at 15 min postinfusion was 1.5 +/- 0.3 ng/ml vs. 0.3 +/- 0.04 ng/ml in the control. SCH 39370 also delayed the disappearance of ir ANF after infusion of the peptide (0.1 microgram/kg/min for 30 min) which increased plasma levels to those observed during volume expansion. This effect was accentuated markedly in rats with bilateral nephrectomy. The hypotensive response to injection of ANF (30 micrograms/kg i.v.) in spontaneously hypertensive rats (-38 +/- 6 mm Hg vs. -13 +/- 2 mm Hg in the control) and the diuretic and natriuretic responses to ANF in normal rats were potentiated by SCH 39370 (30 mg/kg s.c.), respectively. The results suggest that NEP can play a role in ANF disposition in vivo and that potentiation of the biological activities of high doses of ANF by SCH 39370 may be consequent to its inhibitory effect on ANF degradation.(ABSTRACT TRUNCATED AT 250 WORDS)
Sybertz
E J
EJ
Department of Pharmacology, Schering-Plough Research, Bloomfield, New Jersey.
Chiu
P J
PJ
Vemulapalli
S
S
Pitts
B
B
Foster
C J
CJ
Watkins
R W
RW
Barnett
A
A
Haslanger
M F
MF
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D006152:Cyclic GMP / Q000032:analysis; D003900:Desoxycorticosterone / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D012964:Sodium / Q000652:urine
D004151:Dipeptides; C060631:Sch 39370; D003900:Desoxycorticosterone; D009320:Atrial Natriuretic Factor; D012964:Sodium; D008666:Metalloendopeptidases; D006152:Cyclic GMP