Neutral metalloendopeptidase inhibition: a novel means of circulatory modulation.
Inhibition of the enzyme neutral metalloendopeptidase (NEP) potentiates responses to atrial natriuretic factor (ANF) and elicits reductions in blood pressure in deoxycorticosterone acetate sodium (DOCA Na) hypertensive rats. The present study evaluated the role of ANF and bradykinin in the antihypertensive response to NEP inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which NEP inhibition interferes with ANF metabolism was explored. The antihypertensive response to the NEP inhibitors SCH 34826 and 42495 was abruptly reversed by an intravenous injection of a polyclonal antiserum to ANF. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist [thi5,8-D-phe7] bradykinin, indicating that ANF, but not bradykinin, affects this response. The NEP inhibitor SCH 39370 significantly delayed the disappearance of trichloroacetic acid (TCA)-precipitable radioactivity and the appearance of TCA-soluble radioactivity in plasma following an intravenous bolus dose of 125I-ANF(99-126). The effects were enhanced in the presence of the C-receptor ligand des[gln18,ser19,gly20,leu21,gly22]r ANF(4-23)-NH2. These data suggest that the two clearance mechanisms interact to govern plasma levels of ANF.
Sybertz
E J
EJ
Department of Pharmacology, Schering Plough Research, Bloomfield, New Jersey 07003.
Chiu
P J
PJ
Watkins
R W
RW
Vemulapalli
S
S
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000502:physiology*; D003900:Desoxycorticosterone / Q000009:adverse effects; D004148:Dioxolanes / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012982:Sodium, Dietary / Q000009:adverse effects
D004148:Dioxolanes; D004151:Dipeptides; D012982:Sodium, Dietary; C056319:Sch 34826; C060631:Sch 39370; C069018:SCH 42495; D003900:Desoxycorticosterone; D009320:Atrial Natriuretic Factor; D008715:Methionine; D015260:Neprilysin; D001920:Bradykinin