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

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.

[1]  A. Howlett.  Cannabinoid receptor signaling. , 2005, Handbook of experimental pharmacology.

[2]  D. Fegley,et al.  Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Seagard,et al.  Differential endocannabinoid regulation of baroreflex-evoked sympathoinhibition in normotensive versus hypertensive rats , 2009, Autonomic Neuroscience.

[4]  M. Anand-Srivastava,et al.  Enhanced expression of Gialpha protein and adenylyl cyclase signaling in aortas from 1 kidney 1 clip hypertensive rats. , 2006, Canadian journal of physiology and pharmacology.

[5]  A. Makriyannis,et al.  The cannabinergic system as a target for anti-inflammatory therapies. , 2006, Current topics in medicinal chemistry.

[6]  K. Mackie,et al.  Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. , 2005, The Journal of clinical investigation.

[7]  M. Anand-Srivastava,et al.  Enhanced expression of Giα protein and adenylyl cyclase signaling in aortas from 1 kidney 1 clip hypertensive ratsThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference. , 2006 .

[8]  J. de Champlain,et al.  Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase. , 1998, Cardiovascular research.

[9]  G. Kunos.  The hepatic α1-adrenoceptor , 1984 .

[10]  A. Makriyannis,et al.  Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: Drug-discovery strategies , 2009, International review of psychiatry.

[11]  F. Salvi,et al.  A human fatty acid amide hydrolase (FAAH) functional gene variant is associated with lower blood pressure in young males. , 2008, American journal of hypertension.

[12]  P. Pacher,et al.  The Endocannabinoid System as an Emerging Target of Pharmacotherapy , 2006, Pharmacological Reviews.

[13]  Pál Pacher,et al.  Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats , 2008, Nature Protocols.

[14]  J. Seagard,et al.  Anandamide content and interaction of endocannabinoid/GABA modulatory effects in the NTS on baroreflex-evoked sympathoinhibition. , 2004, American journal of physiology. Heart and circulatory physiology.

[15]  S. Schinner,et al.  Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice , 2009 .

[16]  Dale L Boger,et al.  Discovering potent and selective reversible inhibitors of enzymes in complex proteomes , 2003, Nature Biotechnology.

[17]  B. Szabo,et al.  The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[18]  B. Lutz,et al.  Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors , 2008, Neuropharmacology.

[19]  S. Gaetani,et al.  Modulation of anxiety through blockade of anandamide hydrolysis , 2003, Nature Medicine.

[20]  Marya Liimatta,et al.  Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. , 2007, Biochemistry.

[21]  M. Seierstad,et al.  Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors. , 2008, Journal of medicinal chemistry.

[22]  R. Mangieri,et al.  Fatty Acid Amide Hydrolase Inhibition Heightens Anandamide Signaling Without Producing Reinforcing Effects in Primates , 2008, Biological Psychiatry.

[23]  C. Thibault,et al.  Enhanced expression of Gi-protein precedes the development of blood pressure in spontaneously hypertensive rats. , 1997, Journal of molecular and cellular cardiology.

[24]  P. Guyenet,et al.  Mechanism of the hypotensive action of anandamide in anesthetized rats. , 1996, Hypertension.

[25]  D. R. Compton,et al.  Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. , 1997, The Journal of pharmacology and experimental therapeutics.

[26]  Raymond C Stevens,et al.  Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. , 2009, Chemistry & biology.

[27]  B. Cravatt,et al.  Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase. , 2005, American journal of physiology. Heart and circulatory physiology.

[28]  B. Cravatt,et al.  Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. , 2004, Human molecular genetics.

[29]  Stephen P. Mayfield,et al.  Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides , 1996, Nature.

[30]  D. Murphy,et al.  Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. , 1986, Clinical chemistry.

[31]  D. Piomelli,et al.  FAAH deficiency promotes energy storage and enhances the motivation for food , 2012, International Journal of Obesity.

[32]  D. Piomelli,et al.  Analysis of anandamide, an endogenous cannabinoid substance, and of other natural N-acylethanolamines. , 1995, Prostaglandins, leukotrienes, and essential fatty acids.

[33]  K. Mackie,et al.  Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension , 2004, Circulation.

[34]  C. Fowler,et al.  Differences in the pharmacological properties of rat and chicken brain fatty acid amidohydrolase , 2000, British journal of pharmacology.

[35]  G. Marsicano,et al.  Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. , 2008, The Journal of clinical investigation.

[36]  T. Freund,et al.  Brain monoglyceride lipase participating in endocannabinoid inactivation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  D. Stepp,et al.  Impairment of sympathetic baroreceptor reflexes in obese Zucker rats. , 2007, American journal of physiology. Heart and circulatory physiology.

[38]  D. Kass,et al.  Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. , 1987, Circulation.

[39]  S. Ambudkar,et al.  Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. , 2010, The Journal of clinical investigation.

[40]  U. Schopfer,et al.  Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration. , 2007, Journal of medicinal chemistry.

[41]  Agnes L. Bodor,et al.  The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors , 2010, Nature Neuroscience.

[42]  W. Herzer,et al.  PERTUSSIS TOXIN‐SENSITIVE G‐PROTEINS AND REGULATION OF BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT , 1999, Clinical and experimental pharmacology & physiology.

[43]  D. Deutsch,et al.  Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. , 1993, Biochemical pharmacology.

[44]  B. Cravatt,et al.  Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[45]  W. A. Hill,et al.  Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor. , 1997, Biochemical and biophysical research communications.

[46]  P. Guyenet.  The sympathetic control of blood pressure , 2006, Nature Reviews Neuroscience.