An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats

Anne M. Dorrance, Nicole Rupp, David M. Pollock, John W. Newman, Bruce D. Hammock, John D. Imig

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Soluble epoxide hydrolase (sEH) inhibitors have been demonstrated to have cardiovascular protective actions. This hydrolase enzyme converts fatty acid epoxides to their corresponding diols, and this conversion can alter the biologic activity of these metabolites. We hypothesized that 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a sEH inhibitor, would protect stroke-prone spontaneously hypertensive rats from cerebral ischemia. AUDA was administered to 6-week-old male rats for 6 weeks, during which blood pressure was measured by telemetry. Cerebral ischemia was induced by middle cerebral artery occlusion, the size of the cerebral infarct was assessed after 6 hours of ischemia, and the results were expressed as a percentage of the hemisphere infarcted (%HI). Vascular structure and function were assessed using a pressurized arteriograph. Plasma levels of AUDA at the end of the treatment period averaged 5.0 ± 0.4 ng/mL, and the urinary excretion rate was 99 ± 21 ng/d. AUDA-treated rats had significantly smaller cerebral infarcts than control rats (36 ± 4% vs 53 ± 4% HI, treated versus control, P < 0.05, n = 6). This difference occurred independently of changes in blood pressure. AUDA treatment increased the passive compliance of the cerebral vessels but had no effect on vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.

Original languageEnglish (US)
Pages (from-to)842-848
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume46
Issue number6
DOIs
StatePublished - Dec 2005

Fingerprint

Epoxide Hydrolases
Inbred SHR Rats
Stroke
Brain Ischemia
Blood Vessels
Blood Pressure
Telemetry
Middle Cerebral Artery Infarction
Epoxy Compounds
Hydrolases
Compliance
12-(3-adamantan-1-ylureido)dodecanoic acid
Fatty Acids
Ischemia
Enzymes

Keywords

  • Epoxyeicosatrienoic acids
  • Hypertension
  • Ischemia
  • Soluble expoxide hydrolase

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. / Dorrance, Anne M.; Rupp, Nicole; Pollock, David M.; Newman, John W.; Hammock, Bruce D.; Imig, John D.

In: Journal of Cardiovascular Pharmacology, Vol. 46, No. 6, 12.2005, p. 842-848.

Research output: Contribution to journalArticle

Dorrance, Anne M. ; Rupp, Nicole ; Pollock, David M. ; Newman, John W. ; Hammock, Bruce D. ; Imig, John D. / An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. In: Journal of Cardiovascular Pharmacology. 2005 ; Vol. 46, No. 6. pp. 842-848.
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