title: Endothelin-mediated in vivo pressor responses following TRPV1 activation.
abstract: Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1((-/-))], db/db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the α-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 μg/kg) dose dependently increased MAP in control mice (5.7 ± 1.6, 11.7 ± 2.1, 25.4 ± 3.4, and 51.6 ± 3.9%), which was attenuated in db/db mice (3.4 ± 2.1, 3.9 ± 2.1, 7.0 ± 3.3, and 17.9 ± 6.2%). TRPV1((-/-)) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ET(A) /ET(B)). Inhibition of ET(A) receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ET(A) and ET(B) receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ET(A) receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.
authors.affiliation: Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio 44272, USA.
authors.forename: Vahagn A
authors.initials: VA
authors.lastname: Ohanyan
authors.forename: Giacinta
authors.initials: G
authors.lastname: Guarini
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.forename: Phani K
authors.initials: PK
authors.lastname: Talasila
authors.forename: Priya
authors.initials: P
authors.lastname: Raman
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Haney
authors.forename: J Gary
authors.initials: JG
authors.lastname: Meszaros
authors.forename: Derek S
authors.initials: DS
authors.lastname: Damron
authors.forename: Ian N
authors.initials: IN
authors.lastname: Bratz
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D001381:Azepines / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004151:Dipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007211:Indoles / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010656:Phenylephrine / Q000008:administration & dosage; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
chemical_list: D000316:Adrenergic alpha-Agonists; D001381:Azepines; D001713:Biphenyl Compounds; D004151:Dipeptides; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; C098287:IRL 2500; D007211:Indoles; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014662:Vasoconstrictor Agents; C079574:FR 139317; D010656:Phenylephrine; D002211:Capsaicin