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

doi:10.1016/j.chembiol.2010.08.013

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 journal › Article › peer-review

81 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 language	English
Pages (from-to)	1256-1266
Number of pages	11
Journal	Chemistry and Biology
Volume	17
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2010.08.013
State	Published - 24 Nov 2010
Externally published	Yes

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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10.1016/j.chembiol.2010.08.013

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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. (2010). Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects. Chemistry and Biology, 17(11), 1256-1266. https://doi.org/10.1016/j.chembiol.2010.08.013

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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.",

author = "Grzegorz Godlewski and Alapafuja, {Shakiru O.} and S{\'a}ndor B{\'a}tkai and Nikas, {Spyros P.} and Resat Cinar and L{\'a}szl{\'o} Offert{\'a}ler and Douglas Osei-Hyiaman and Jie Liu and Bani Mukhopadhyay and Judith Harvey-White and Joseph Tam and Karel Pacak and Blankman, {Jacqueline L.} and Cravatt, {Benjamin F.} and Alexandros Makriyannis and George Kunos",

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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doi = "10.1016/j.chembiol.2010.08.013",

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Godlewski, G, Alapafuja, SO, Bátkai, S, Nikas, SP, Cinar, R, Offertáler, L, Osei-Hyiaman, D, Liu, J, Mukhopadhyay, B, Harvey-White, J, Tam, J, Pacak, K, Blankman, JL, Cravatt, BF, Makriyannis, A & Kunos, G 2010, 'Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects', Chemistry and Biology, vol. 17, no. 11, pp. 1256-1266. https://doi.org/10.1016/j.chembiol.2010.08.013

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T1 - Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects

AU - Godlewski, Grzegorz

AU - Alapafuja, Shakiru O.

AU - Bátkai, Sándor

AU - Nikas, Spyros P.

AU - Cinar, Resat

AU - Offertáler, László

AU - Osei-Hyiaman, Douglas

AU - Liu, Jie

AU - Mukhopadhyay, Bani

AU - Harvey-White, Judith

AU - Tam, Joseph

AU - Pacak, Karel

AU - Blankman, Jacqueline L.

AU - Cravatt, Benjamin F.

AU - Makriyannis, Alexandros

AU - Kunos, George

N1 - 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.

PY - 2010/11/24

Y1 - 2010/11/24

N2 - 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.

AB - 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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SN - 1074-5521

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JF - Chemistry and Biology

IS - 11

ER -

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

Abstract

Bibliographical note

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