Abstract
Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (Vmax) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1- ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg-1·day-1 for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg (P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml (P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15-trans-EET was more potent (ED50 10-10 M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED50 10-9 M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and transisomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 300 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2011 |
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Keywords
- Cytochrome P-450
- Epoxyeicosatrienoic acids
- Hypertension
- Soluble epoxide hydrolase
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Cite this
Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats. / Jiang, Houli; Quilley, John; Doumad, Anabel B.; Zhu, Angela G.; Falck, J R; Hammock, Bruce D.; Stier, Charles T.; Carroll, Mairead A.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 300, No. 6, 06.2011.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats
AU - Jiang, Houli
AU - Quilley, John
AU - Doumad, Anabel B.
AU - Zhu, Angela G.
AU - Falck, J R
AU - Hammock, Bruce D.
AU - Stier, Charles T.
AU - Carroll, Mairead A.
PY - 2011/6
Y1 - 2011/6
N2 - Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (Vmax) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1- ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg-1·day-1 for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg (P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml (P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15-trans-EET was more potent (ED50 10-10 M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED50 10-9 M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and transisomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.
AB - Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (Vmax) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1- ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg-1·day-1 for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg (P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml (P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15-trans-EET was more potent (ED50 10-10 M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED50 10-9 M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and transisomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.
KW - Cytochrome P-450
KW - Epoxyeicosatrienoic acids
KW - Hypertension
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=79958041570&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958041570&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.01267.2010
DO - 10.1152/ajpheart.01267.2010
M3 - Article
C2 - 21398593
AN - SCOPUS:79958041570
VL - 300
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 6
ER -