title: Cardioprotective effects of fatty acid amide hydrolase inhibitor URB694, in a rodent model of trait anxiety.
abstract: In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ventricular tachyarrhythmias, and (iv) corrected alterations of ventricular refractoriness. The anti-arrhythmic effect of URB694 was prevented by pharmacological blockade of the cannabinoid type 1 (CB1), but not of the CB2, receptor. These findings suggest that URB694 exerts anxiolytic-like and cardioprotective effects in HAB rats, the latter via anandamide-mediated activation of CB1 receptors. Thus, pharmacological inhibition of FAAH might be a viable pharmacological strategy for the treatment of anxiety-related cardiac dysfunction.
authors.affiliation: Department of Neuroscience, University of Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Carnevali
authors.affiliation: Department of Pharmacy, University of Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Department of Life Sciences, University of Parma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Life Sciences, University of Parma, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Macchi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Italy.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Italy.
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.affiliation: Department of Behavioural and Molecular Neurobiology, University of Regensburg, Germany.
authors.forename: Inga D
authors.initials: ID
authors.lastname: Neumann
authors.affiliation: Department of Pharmacy, University of Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Department of Pharmacy, University of Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Department of Neuroscience, University of Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sgoifo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology* / Q000523:psychology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D001713:Biphenyl Compounds; D002219:Carbamates; D002316:Cardiotonic Agents; D007545:Isoproterenol; D000099252:Fatty Acid Amide Hydrolases; C555899:cyclohexyl carbonic acid 3'-carbamoyl-3-yl ester