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 antihyper...

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Bibliographic Details
Published inJournal of hypertension. Supplement Vol. 8; no. 7; p. S161
Main Authors Sybertz, Jr, E J, Chiu, P J, Watkins, R W, Vemulapalli, S
Format Journal Article
LanguageEnglish
Published England 01.12.1990
Subjects
Animals
Atrial Natriuretic Factor - physiology
Blood Pressure - drug effects
Bradykinin - physiology
Desoxycorticosterone - adverse effects
Dioxolanes - pharmacology
Dipeptides - pharmacology
Hypertension - drug therapy
Hypertension - etiology
Hypertension - metabolism
Male
Methionine - analogs & derivatives
Neprilysin - antagonists & inhibitors
Neprilysin - pharmacology
Rats
Rats, Inbred Strains
Sodium, Dietary - adverse effects
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Summary: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.
ISSN:0952-1178