Mechanisms of the natriuretic effects of neutral endopeptidase inhibition in Dahl salt-sensitive and salt-resistant rats.
To explore the mechanisms of the renal effects of neutral endopeptidase (NEP) inhibition, the effects of an NEP inhibitor, candoxatril (UK 79,300; UK), in Dahl salt-sensitive (SS) and salt-resistant (SR) rats were examined. UK dose-dependently decreased blood pressure (BP) in SS rats (20 mg/kg: 174 +/- 5 vs. 155 +/- 8 mm Hg, p < 0.01) but not in SR rats. Urinary sodium excretion (UNaV) of both rat strains receiving high-salt diets was increased to a greater extent than that of rats receiving low-salt diets. Basal plasma atrial natriuretic peptide (ANP) level in hypertensive SS rats was higher than in SR rats (192 +/- 18 vs. 118 +/- 24 pg/ml, p < 0.05). UK increased ANP levels in the plasma and urine two- and 11-fold, respectively. UK-induced increases in UNaV, urinary cyclic GMP, and plasma ANP concentrations were significantly augmented by coadministration of a clearance receptor agonist, C-ANF(4-23) or brain natriuretic peptide (BNP). Thus, the effects of NEP inhibition appear to be potentiated by the reduced receptor-mediated metabolism of ANP. This may explain the greater response to the NEP inhibitor in Dahl rats with hypertension or high-salt feeding.
Hirata
Y
Y
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Suzuki
E
E
Hayakawa
H
H
Matsuoka
H
H
Sugimoto
T
T
Kangawa
K
K
Matsuo
H
H
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000494:pharmacology / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D007189:Indans / Q000494:pharmacology*; D009318:Natriuresis / Q000187:drug effects*; D020097:Natriuretic Peptide, Brain; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012982:Sodium, Dietary / Q000494:pharmacology*
D007189:Indans; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011422:Propionates; D012982:Sodium, Dietary; C065367:atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D015260:Neprilysin