Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension.
In stroke-prone spontaneously hypertensive rats (SHRSP) end-organ damage is markedly accelerated by high-salt (HS) intake. Since epoxyeicosatrienoic acids (EETs) possess vasodepressor and natriuretic activities, we examined whether a soluble epoxide hydrolase (sEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), to inhibit the metabolism of EETs, would protect against pathologic changes in SHRSP. Seven-week-old male SHRSP were treated as follows: normal salt (NS), NS + AUDA, HS and HS + AUDA. Systolic blood pressure (SBP) (205 +/- 4 v 187 +/- 7 mmHg) and proteinuria (3.7 +/- 0.2 v 2.6 +/- 0.2 mg/6 h), but not plasma EETs (11.0 +/- 0.9 v 9.7 +/- 1.1 ng/ml), were significantly increased at 9 weeks of age in HS v NS SHRSP. HS was associated with fibrinoid degeneration and hypertrophy of arterioles in the kidney and perivascular fibrosis and contraction band necrosis in the heart. AUDA ameliorated these early salt-dependent changes in saline-drinking SHRSP and increased plasma levels of EETs but did not affect water and electrolyte excretion. sEH inhibition may provide a therapeutic strategy for treating salt-sensitive hypertension and its sequelae.
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA.
Jing
J
Li
Mairead A
MA
Carroll
Praveen N
PN
Chander
John R
JR
Falck
Bhavani
B
Sangras
Charles T
CT
Stier
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004537:Eicosanoic Acids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D053503:Epithelial Sodium Channels / Q000502:physiology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000517:prevention & control*; D007850:Lauric Acids / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D012965:Sodium Chloride / Q000009:adverse effects; D020521:Stroke / Q000453:epidemiology
C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D004537:Eicosanoic Acids; D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D007850:Lauric Acids; D012965:Sodium Chloride; D004851:Epoxide Hydrolases; D000218:Adamantane