Inhibition of neutral endopeptidase (EC 3.4.24.11) leads to an atrial natriuretic factor-mediated natriuretic, diuretic and antihypertensive response in rodents.
1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 3.4.24.11) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor. 2. (+/-)-Candoxatrilat, a selective neutral endopeptidase inhibitor, potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (+/-)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum. 3. (+/-)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum. 4. These data demonstrate that the neutral endopeptidase inhibitor (+/-)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents, and that these effects are mediated via endogenous atrial natriuretic factor.
Shepperson
N B
NB
Pfizer Central Research, Sandwich, Kent, U.K.
Barclay
P L
PL
Bennett
J A
JA
Samuels
G M
GM
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000276:immunology / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003900:Desoxycorticosterone; D004231:Diuresis / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D007106:Immune Sera / Q000008:administration & dosage; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains
D003509:Cyclohexanecarboxylic Acids; D007106:Immune Sera; D003900:Desoxycorticosterone; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D015260:Neprilysin