title: G protein-coupled bile acid receptor 1 stimulation mediates arterial vasodilation through a K(Ca)1.1 (BK(Ca))-dependent mechanism.
abstract: Bile acids (BAs) and BA receptors, including G protein-coupled bile acid receptor 1 (GPBAR1), represent novel targets for the treatment of metabolic and inflammatory disorders. However, BAs elicit myriad effects on cardiovascular function, although this has not been specifically ascribed to GPBAR1. This study was designed to test whether stimulation of GPBAR1 elicits effects on cardiovascular function that are mechanism based that can be identified in acute ex vivo and in vivo cardiovascular models, to delineate whether effects were due to pathways known to be modulated by BAs, and to establish whether a therapeutic window between in vivo cardiovascular liabilities and on-target efficacy could be defined. The results demonstrated that the infusion of three structurally diverse and selective GPBAR1 agonists produced marked reductions in vascular tone and blood pressure in dog, but not in rat, as well as reflex tachycardia and a positive inotropic response, effects that manifested in an enhanced cardiac output. Changes in cardiovascular function were unrelated to modulation of the levothyroxine/thyroxine axis and were nitric oxide independent. A direct effect on vascular tone was confirmed in dog isolated vascular rings, whereby concentration-dependent decreases in tension that were tightly correlated with reductions in vascular tone observed in vivo and were blocked by iberiotoxin. Compound concentrations in which cardiovascular effects occurred, both ex vivo and in vivo, could not be separated from those necessary for modulation of GPBAR1-mediated efficacy, resulting in project termination. These results are the first to clearly demonstrate direct and potent peripheral arterial vasodilation due to GPBAR1 stimulation in vivo through activation of large conductance Ca(2+) activated potassium channel K(Ca)1.1.
authors.affiliation: Departments of Cardiometabolic Diseases Research (R.M.F., K.J.N., S.G.N.M., A.M.), Immunology and Inflammation (L.P., L.K.M.), and Medicinal Chemistry (D.J.S., K.E.G., R.M.D., D.K., J.L., S.S., H.Y., C.H., M.C.C., E.R.H.), Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Khing Jow
authors.initials: KJ
authors.lastname: Ng
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Nodop Mazurek
authors.forename: Lori
authors.initials: L
authors.lastname: Patnaude
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Skow
authors.forename: Akalushi
authors.initials: A
authors.lastname: Muthukumarana
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Gilpin
authors.forename: Roger M
authors.initials: RM
authors.lastname: Dinallo
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuzmich
authors.forename: John
authors.initials: J
authors.lastname: Lord
authors.forename: Sulagna
authors.initials: S
authors.lastname: Sanyal
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cerny
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cerny
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Hickey
authors.forename: Louise K
authors.initials: LK
authors.lastname: Modis
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000097:blood; D016466:CHO Cells; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives; D004285:Dogs; D019332:Endothelin-1 / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013974:Thyroxine / Q000097:blood; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D016207:Cytokines; D019332:Endothelin-1; C473772:GPBAR1 protein, human; C518268:Gpbar1 protein, rat; D007093:Imidazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C045305:2,4-dinitrofluorobenzene sulfonic acid; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D004139:Dinitrofluorobenzene; D000242:Cyclic AMP; D013974:Thyroxine