RT Journal Article
SR Electronic
T1 G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a K<sub>Ca</sub>1.1 (BK<sub>Ca</sub>)–Dependent Mechanism
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 421
OP 431
DO 10.1124/jpet.113.210005
VO 348
IS 3
A1 Ryan M. Fryer
A1 Khing Jow Ng
A1 Suzanne G. Nodop Mazurek
A1 Lori Patnaude
A1 Donna J. Skow
A1 Akalushi Muthukumarana
A1 Kyle E. Gilpin
A1 Roger M. Dinallo
A1 Daniel Kuzmich
A1 John Lord
A1 Sulagna Sanyal
A1 Hui Yu
A1 Christian Harcken
A1 Matthew A. Cerny
A1 Eugene R. Hickey
A1 Louise K. Modis
YR 2014
UL http://jpet.aspetjournals.org/content/348/3/421.abstract
AB 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 Ca2+ activated potassium channel KCa1.1.