title: Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects.
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.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, MD 20852, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.forename: Shakiru O
authors.initials: SO
authors.lastname: Alapafuja
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.forename: László
authors.initials: L
authors.lastname: Offertáler
authors.forename: Douglas
authors.initials: D
authors.lastname: Osei-Hyiaman
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000476:Alkanesulfonates / Q000737:chemistry* / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000627:therapeutic use; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000476:Alkanesulfonates; D000581:Amidohydrolases; D000959:Antihypertensive Agents; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D010636:Phenols; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C556520:AM 3506; C078814:anandamide