Cardiovascular Drug Reviews Vol. 25, No. 1, pp. 46–60 C  2007 The Authors Journal compilation C  2007 Blackwell Publishing Inc. Oleamide: A Fatty Acid Amide Signaling Molecule in the Cardiovascular System? C. Robin Hiley and Pui Man Hoi Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK Keywords: Blood pressure — Cannabinoid receptors — Endocannabi- noids — Endothelial cells — FAAH — Fatty acid amide hydrolase — Gap junctions — Hypothermia — Oleamide—TRPV1 — Vanilloid receptor — Vascular smooth muscle. ABSTRACT Oleamide (cis-9,10-octadecenoamide), a fatty acid primary amide discovered in the cerebrospinal fluid of sleep-deprived cats, has a variety of actions that give it potential as a signaling molecule, although these actions have not been extensively investigated in the cardiovascular system. The synthetic pathway probably involves synthesis of oleoylglycine and then conversion to oleamide by peptidylglycine α-amidating monooxygenase (PAM); breakdown of oleamide is by fatty acid amide hydrolase (FAAH). Oleamide interacts with voltage-gated Na + channels and allosterically with GABA A and 5-HT 7 receptors as well as having cannabinoid-like actions. The latter have been suggested to be due to potentia- tion of the effects of endocannabinoids such as anandamide by inhibiting FAAH-mediated hydrolysis. This might underlie an “entourage effect” whereby co-released endogenous nonagonist congeners of endocannabinoids protect the active molecule from hydrolysis by FAAH. However, oleamide has direct agonist actions at CB 1 cannabinoid receptors and also activates the TRPV1 vanilloid receptor. Other actions include inhibition of gap-junctional communication, and this might give oleamide a role in myocardial development. Many of these actions are absent from the trans isomer of 9,10-octadecenoamide. One of the most potent actions of oleamide is vasodilation. In rat small mesenteric artery the response does not involve CB 1 cannabinoid receptors but another pertussis toxin-sensitive, G protein– coupled receptor, as yet unidentified. This receptor is sensitive to rimonabant and O-1918, Address correspondence and reprint requests to: Dr. C. Robin Hiley, Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK. Tel.: +44-1223-334018; Fax: +44-1223-334100; E-mail: crh1@cam.ac.uk Conflict of Interest: All authors declare that they have no conflict of interest in this study. 46