Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects

Grzegorz Godlewski, Shakiru O. Alapafuja, Sándor Bátkai, Spyros P. Nikas, Resat Cinar, László Offertáler, Douglas Osei-Hyiaman, Jie Liu, Bani Mukhopadhyay, Judith Harvey-White, Joseph Tam, Karel Pacak, Jacqueline L. Blankman, Benjamin F. Cravatt, Alexandros Makriyannis, George Kunos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB1 receptor-mediated cardiovascular depression is related to increased G protein coupling of CB1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH-/- mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.

Original languageAmerican English
Pages (from-to)1256-1266
Number of pages11
JournalChemistry and Biology
Volume17
Issue number11
DOIs
StatePublished - 24 Nov 2010
Externally publishedYes

Bibliographical note

Funding Information:
We thank Prof. B. Lutz and Dr. G. Marsicano for providing CB 1 floxed mice used to generate the liver-specific CB 1 −/− mice.This work was supported by funds from the intramural program of NIAAA.

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