Abstract
The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 992-998 |
| Number of pages | 7 |
| Journal | Circulation Research |
| Volume | 87 |
| Issue number | 11 |
| State | Published - Nov 24 2000 |
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Keywords
- Cytochrome P450
- Dihydroxyeicosatrienoic acids
- Epoxyeicosatrienoic acids
- Hypertension
- Soluble epoxide hydrolase
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. / Yu, Zhigang; Xu, Fengyun; Huse, Linn M.; Morisseau, Christophe; Draper, Alison J.; Newman, John W.; Parker, Carol; Graham, LeRae; Engler, Marguerite M.; Hammock, Bruce D.; Zeldin, Darryl C.; Kroetz, Deanna L.
In: Circulation Research, Vol. 87, No. 11, 24.11.2000, p. 992-998.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids
AU - Yu, Zhigang
AU - Xu, Fengyun
AU - Huse, Linn M.
AU - Morisseau, Christophe
AU - Draper, Alison J.
AU - Newman, John W.
AU - Parker, Carol
AU - Graham, LeRae
AU - Engler, Marguerite M.
AU - Hammock, Bruce D.
AU - Zeldin, Darryl C.
AU - Kroetz, Deanna L.
PY - 2000/11/24
Y1 - 2000/11/24
N2 - The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.
AB - The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.
KW - Cytochrome P450
KW - Dihydroxyeicosatrienoic acids
KW - Epoxyeicosatrienoic acids
KW - Hypertension
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=0034711488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034711488&partnerID=8YFLogxK
M3 - Article
C2 - 11090543
AN - SCOPUS:0034711488
VL - 87
SP - 992
EP - 998
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 11
ER -