PMID- 21451419
OWN - NLM
STAT- MEDLINE
DCOM- 20110915
LR  - 20131121
IS  - 1473-5598 (Electronic)
IS  - 0263-6352 (Linking)
VI  - 29
IP  - 6
DP  - 2011 Jun
TI  - Soluble epoxide hydrolase inhibition prevents coronary endothelial dysfunction in 
      mice with renovascular hypertension.
PG  - 1128-35
LID - 10.1097/HJH.0b013e328345ef7b [doi]
AB  - OBJECTIVES: The study addresses the hypothesis that endothelial dysfunction in 
      experimental arterial hypertension can be related to an alteration in 
      epoxyeicosatrienoic acids (EETs) pathway and can be prevented by the inhibition 
      of EETs degradation by soluble epoxide hydrolase (sEH). METHODS AND RESULTS: 
      Arterial hypertension was induced in FVB/N mice by renal artery stenosis 
      ('two-kidney-one-clip', 2K1C). Seven weeks after surgery, increased aortic 
      pressures (Millar tonometer; Millar Instruments, Houston, Texas, USA) and cardiac 
      hypertrophy (echocardiography) were present in 2K1C mice as compared with control 
      mice. Left coronary artery endothelium-dependent relaxations to acetylcholine 
      were decreased in 2K1C mice without modification in the relaxing responses to 
      NS309 and NS1619, the openers of calcium-activated potassium channels mediating 
      the hyperpolarizing effect of EETs. The inhibitors of the EET-synthesizing 
      enzymes cytochrome P450 epoxygenases, fluconazole and 
      N-methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MSPPOH), reduced the 
      coronary relaxations to acetylcholine in control but not in 2K1C mice. The sEH 
      expression was increased in 2K1C mice. The sEH inhibitor 
      12-(3-adamantan-1-yl-ureido)dodecanoic acid administered for 2 weeks starting 5 
      weeks after surgery in 2K1C mice (25 mg/l in drinking water) reduced aortic 
      pressures and cardiac hypertrophy, improved the coronary relaxations to 
      acetylcholine and restored the inhibitory effect of fluconazole and MSPPOH on 
      acetylcholine-induced relaxations, without modifying the relaxations to NS309 and 
      NS1619. CONCLUSION: These results demonstrate that a reduced EET-mediated 
      relaxations related to an increased degradation by sEH contributes to coronary 
      endothelial dysfunction in 2K1C hypertensive mice. Inhibiting sEH prevents 
      endothelial dysfunction by restoring EET-mediated relaxations and thus, could 
      represent a promising pharmacological intervention to limit cardiovascular 
      morbidity and mortality in arterial hypertension.
FAU - Gao, Ji
AU  - Gao J
AD  - From the INSERM U644, France. jeremy.bellien@chu-rouen.fr
FAU - Bellien, Jeremy
AU  - Bellien J
FAU - Gomez, Elodie
AU  - Gomez E
FAU - Henry, Jean-Paul
AU  - Henry JP
FAU - Dautreaux, Brigitte
AU  - Dautreaux B
FAU - Bounoure, Frederic
AU  - Bounoure F
FAU - Skiba, Mohamed
AU  - Skiba M
FAU - Thuillez, Christian
AU  - Thuillez C
FAU - Richard, Vincent
AU  - Richard V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Hypertens
JT  - Journal of hypertension
JID - 8306882
RN  - 0 (Amides)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide)
RN  - 8VZV102JFY (Fluconazole)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Amides/pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - Coronary Vessels/*drug effects/enzymology
MH  - Echocardiography
MH  - Endothelium, Vascular/*drug effects/enzymology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Epoxide Hydrolases/*antagonists & inhibitors
MH  - Fluconazole/pharmacology
MH  - Hypertension/*physiopathology
MH  - Kidney/*physiopathology
MH  - Male
MH  - Mice
EDAT- 2011/04/01 06:00
MHDA- 2011/09/16 06:00
CRDT- 2011/04/01 06:00
PHST- 2011/04/01 06:00 [entrez]
PHST- 2011/04/01 06:00 [pubmed]
PHST- 2011/09/16 06:00 [medline]
AID - 10.1097/HJH.0b013e328345ef7b [doi]
PST - ppublish
SO  - J Hypertens. 2011 Jun;29(6):1128-35. doi: 10.1097/HJH.0b013e328345ef7b.