Inhibition of soluble epoxide hydrolase limits niacin-induced vasodilation in mice.

Abstract

BACKGROUND:

The use of niacin in the treatment of dyslipidemias is limited by the common side effect of cutaneous vasodilation, commonly termed flushing. Flushing is thought to be due to release of the vasodilatory prostanoids prostaglandin D2 (PGD2) and prostaglandin E2 from arachidonic acid metabolism through the cyclooxygenase pathway. Arachidonic acid is also metabolized by the cytochrome P450 system, which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH).

METHODS:

These experiments used an established murine model in which ear tissue perfusion was measured by laser Doppler to test the hypothesis that inhibition of sEH would limit niacin-induced flushing.

RESULTS:

Niacin-induced flushing was reduced from 506 ± 126% to 213 ± 39% in sEH knockout animals. Pharmacologic treatment with 3 structurally distinct sEH inhibitors similarly reduced flushing in a dose-dependent manner, with maximal reduction to 143% ± 15% of baseline flow using a concentration of 1 mg/kg TPAU (1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea). Systemically administered PGD2 caused ear vasodilation, which was not changed by either pharmacologic sEH inhibition or sEH gene deletion.

CONCLUSIONS:

Inhibition of sEH markedly reduces niacin-induced flushing in this model without an apparent effect on the response to PGD2. sEH inhibition may be a new therapeutic approach to limit flushing in humans.

• Authors: Ahmet B Inceoglu, Heather L Clifton, Jun Yang, Christine Hegedus, Bruce D Hammock, Saul Schaefer
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 60 Issue 1 Pg. 70-5 (Jul 2012) ISSN: 1533-4023 [Electronic] United States
• PMID: 22526297 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl)urea
• Phenylurea Compounds
• Piperidines
• Vasodilator Agents
• Niacin
• Arachidonic Acid
• Epoxide Hydrolases
• Dinoprostone
• Prostaglandin D2

Topics

• Animals
• Arachidonic Acid (metabolism)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Epoxide Hydrolases (genetics, metabolism)
• Flushing (chemically induced)
• Gene Deletion
• Laser-Doppler Flowmetry
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Niacin (administration & dosage, adverse effects, pharmacology)
• Phenylurea Compounds (pharmacology)
• Piperidines (pharmacology)
• Prostaglandin D2 (administration & dosage, metabolism)
• Vasodilation (drug effects)
• Vasodilator Agents (administration & dosage, adverse effects, pharmacology)