Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects
Open accessAbstract
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.
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Systemic administration of AM3506 prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction.
“More recently, systemic administration of a novel, potent FAAH inhibitor, AM3506 [100], prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction [50].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [100]
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- Authors
- Godlewski, G., Alapafuja, S. O., Bátkai, S., Nikas, S. P., Cinar, R., Offertáler, L., Osei-Hyiaman, D., Liu, J., Mukhopadhyay, B., Harvey-White, J., Tam, J., Pacak, K., Blankman, J. L., Cravatt, B. F., Makriyannis, A., & Kunos, G.
- Affiliations
- National Institutes of Health (US)
- Northeastern University (US)
- Scripps Research Institute (US)
- Corresponding author
- Makriyannis, Alexandros
- Kunos, George
- ORCID
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 17
- Issue
- 11
- Pages
- 1256-1266
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC3003779
- OpenAlex
- W2036073332
- Cited by
- 95
- References
- 45
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 3 · 2013: 10 · 2012: 9
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (ZIAAA000351)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- fatty acid amide hydrolase, FAAH inhibitors, anandamide, endocannabinoids, hypertension, spontaneously hypertensive rats, CB1 receptor, sympathetic tone, cardiac contractility, G protein coupling, hepatic metabolism, insulin resistance, hyperglycemia
- MeSH terms
- Fatty Acid Amide Hydrolases, Alkanesulfonates, Amidohydrolases, Animals, Antihypertensive Agents, Arachidonic Acids, Brain, Disease Models, Animal, Enzyme Inhibitors, Hypertension, Male, Phenols, Mice, Knockout, Receptor, Cannabinoid, CB1, Mice, Rats, Polyunsaturated Alkamides, Endocannabinoids
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