Effects of acute and chronic blockade of neutral endopeptidase with Sch 34826 on NaCl-sensitive hypertension in spontaneously hypertensive rats.
We have previously demonstrated that dietary NaCl supplementation is associated with increased circulating atrial natriuretic peptide (ANP) levels in Wistar-Kyoto (WKY) rats but not in spontaneously hypertensive rats (SHR), and that replacement with exogenous ANP prevents NaCl-sensitive hypertension in NaCl-sensitive SHR (SHR-S). The current study tested the hypothesis that chronic administration of the neutral endopeptidase (NEP) inhibitor Sch 34826 prevents NaCl sensitive hypertension in SHR-S by increasing endogenous ANP. Male SHR-S received Sch 34826 (90 mg/kg/day) or vehicle by gavage for 4 weeks beginning immediately before the initiation of 1% or 8% NaCl diets at age 7 weeks. Sch 34826 prevented the increase in arterial pressure in response to 8% NaCl in SHR-S, but had no effect on blood pressure in 1% NaCl fed SHR-S; plasma ANP levels were increased by 63 and 68% in the 1% and 8% NaCl groups, respectively, in response to Sch 34826. To examine the mechanism(s) of the antihypertensive effect of Sch 34826 in NaCl-supplemented SHR-S, a single dose (90 mg/kg) of Sch 34826 or vehicle was administered by gavage to SHR-S that had consumed 1% or 8% NaCl diets for 3 weeks. Sch 34826 abolished the NaCl-induced increase in blood pressure 3 h after treatment in 8% NaCl fed SHR-S, but had no effect in SHR-S fed the 1% NaCl diet. This effect was associated with increased urine volume and urinary sodium, ANP, and cyclic GMP in 8% NaCl fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)
Jin
H
H
Department of Medicine, University of Alabama, Birmingham.
Mathews
C
C
Chen
Y F
YF
Yang
R
R
Wyss
J M
JM
Esunge
P
P
Oparil
S
S
D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000652:urine; D004148:Dioxolanes / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology* / Q000652:urine; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011921:Rats, Inbred WKY; D012964:Sodium / Q000652:urine; D012965:Sodium Chloride / Q000008:administration & dosage / Q000009:adverse effects*
D000700:Analgesics; D004148:Dioxolanes; D004151:Dipeptides; D011480:Protease Inhibitors; C056319:Sch 34826; D012965:Sodium Chloride; D009320:Atrial Natriuretic Factor; D012964:Sodium; D006152:Cyclic GMP