title: Protective role of cannabinoid CB1 receptors and vascular effects of chronic administration of FAAH inhibitor URB597 in DOCA-salt hypertensive rats.
abstract: OBJECTIVE
  This study examined whether the fall in blood pressure (BP) induced by the chronic inhibition of fatty acid amide hydrolase (FAAH) by URB597 in deoxycorticosterone acetate (DOCA-salt) hypertensive rats correlates with endocannabinoid-mediated vascular changes.
  
  
  METHODS
  Functional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively.
  
  
  RESULTS
  In the DOCA-salt rats, methanandamide-stimulated relaxation was enhanced in sMAs or diminished in aortas. Its vasorelaxant effect in sMAs was sensitive to the antagonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1), capsazepine, in normo- and hypertensive animals and to the antagonist of the cannabinoid CB1 receptors, AM6545, only in DOCA-salt rats. Cannabinoid CB1 receptors were up-regulated merely in DOCA-salt sMAs. URB597 decreased elevated BP in DOCA-salt rats, medial hypertrophy in DOCA-salt aortas. In sMAs it reduced FAAH expression and restored the augmented phenylephrine-induced contraction in the DOCA-salt rats to the level obtained in normotensive controls. In normotensive rats it diminished endothelium-dependent relaxation and increased phenylephrine-induced contraction.
  
  
  CONCLUSIONS
  The study showed the protective role of cannabinoid CB1 receptors in DOCA-salt sMAs. Reduction in BP after chronic administration of the FAAH inhibitor URB597 in DOCA-salt hypertensive rats only partially correlates with structural and functional changes in conductance and resistance vessels, respectively. Caution should be taken in studying cannabinoids and FAAH inhibitors as potential therapeutics, because of their vessel- and model-specific activities, and side effects connected with off-target response and activation of alternative pathways of anandamide metabolism.
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland; Department of Clinical Pharmacy, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland. Electronic address: mabar@umb.edu.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Baranowska-Kuczko
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kozłowska
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kloza
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Karpińska
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Toczek
authors.affiliation: Department of Physiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Harasim
authors.affiliation: Department of Histology and Cytophysiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Kasacka
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malinowska
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology*; D001794:Blood Pressure / Q000502:physiology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002219:Carbamates / Q000008:administration & dosage* / Q000494:pharmacology*; D064791:Desoxycorticosterone Acetate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002211:Capsaicin; D002219:Carbamates; D064791:Desoxycorticosterone Acetate; D009025:Morpholines; D010656:Phenylephrine; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D012965:Sodium Chloride; D000099252:Fatty Acid Amide Hydrolases; C551825:AM6545; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C088155:methanandamide; C071423:capsazepine
keywords: Cannabinoid; DOCA-salt hypertension; FAAH inhibitor; URB597