Mechanisms underlying the augmented responses of deoxycorticosterone acetate-salt hypertensive rats to neutral endopeptidase inhibitors.
OBJECTIVE
To explore the mechanisms for augmented neutral endopeptidase inhibitor-induced natriuresis in deoxycorticosterone acetate (DOCA)-salt rats.


METHODS
We examined effects of a neutral endopeptidase-inhibitor, candoxatril, on plasma and urinary brain natriuretic peptide (BNP) levels, the influence of a specific atrial natriuretic peptide (ANP) receptor antagonist, HS-142-1, on the response to candoxatril, and the renal neutral endopeptidase activity in DOCA-salt rats.


RESULTS
Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats. These effects were associated with a significant rise in the plasma BNP level and the plasma ANP level in DOCA-salt rats. Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril. Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion. Urinary neutral endopeptidase-like activity was greater in DOCA-salt rats than in control rats. Northern blot analysis revealed that the ratio of renal neutral endopeptidase messenger RNA (mRNA) to beta-actin mRNA was comparable between the two groups.


CONCLUSIONS
The neutral endopeptide inhibitor exerted its hypotensive and natriuretic effects mainly via the potentiation of the endogenous natriuretic peptides, including BNP. The augmented response of DOCA-salt rats also seems to be mediated by both the downregulation of clearance receptors and an increase in renal neutral endopeptidase activity.
Hirata
Y
Y
Second Department of Internal Medicine, University of Tokyo, Japan.
Suzuki
Y
Y
Suzuki
E
E
Hayakawa
H
H
Kimura
K
K
Goto
A
A
Omata
M
M
Minamino
N
N
Kangawa
K
K
Matsuo
H
H
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000652:urine; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D006973:Hypertension / Q000139:chemically induced* / Q000652:urine; D007189:Indans / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000652:urine; D011134:Polysaccharides / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride; D015244:Thiorphan / Q000494:pharmacology
D000959:Antihypertensive Agents; C072551:HS 142-1; D007189:Indans; D011134:Polysaccharides; D011422:Propionates; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D015244:Thiorphan; D015260:Neprilysin