title: Activation of CB1receptors by 2-arachidonoylglycerol attenuates vasoconstriction induced by U46619 and angiotensin II in human and rat pulmonary arteries.
abstract: Recent evidence suggests that endocannabinoids acting via cannabinoid CB1receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature. The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A2analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct Gq/11protein-coupled receptors (thromboxane, ANG II type 1, 5-HT2, and α1-adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB1receptor antagonist AM251 (1 μM) and diacylglycerol lipase (2-arachidonoylglycerol synthesis enzyme) inhibitor RHC80267 (40 μM) enhanced contractions induced by U46619 in hPAs and rPAs and by ANG II in rPAs in an endothelium-dependent manner. AM251 did not influence vasoconstrictions induced by 5-HT or phenylephrine in rPAs. The monoacylglycerol lipase (2-arachidonoylglycerol degradation enzyme) inhibitor JZL184 (1 μM), but not the fatty acid amide hydrolase (anandamide degradation enzyme) inhibitor URB597 (1 μM), attenuated contractions evoked by U46619 in hPAs and rPAs and ANG II in rPAs. 2-Arachidonoylglycerol concentration-dependently induced relaxation of hPAs, which was inhibited by endothelium denudation or AM251 and enhanced by JZL184. Expression of CB1receptors was confirmed in hPAs and rPAs using Western blotting and immunohistochemistry. The present study shows the protective interaction between the endocannabinoid system and vasoconstriction in response to U46619 and ANG II in the human and rat pulmonary circulation. U46619 and ANG II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB1receptor-dependent and/or CB1receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction.
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Karpińska
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Baranowska-Kuczko
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kloza
authors.affiliation: Department of Inorganic and Analytical Chemistry, Medical University of Białystok, Białystok, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Ambroz Ewicz
authors.affiliation: Department of Thoracic Surgery, Medical University of Białystok, Białystok, Poland; and.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kozłowski
authors.affiliation: Department of Histology and Cytophysiology, Medical University of Białystok, Białystok, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Kasacka
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malinowska
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland; hkozl@umb.edu.pl.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kozłowska
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000494:pharmacology*; D005260:Female; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001095:Arachidonic Acids; C571130:CNR1 protein, human; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C094503:glyceryl 2-arachidonate
keywords: 2-arachidonoylglycerol; anandamide; cannabinoid receptor type 1; monoacylglycerol lipase; pulmonary artery