G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a K_Ca1.1 (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 21 activated potassium channel K Ca 1.1.

Circulating bile acids predict outcome in critically ill patients

“…Furthermore, alterations of BA metabolism have been found in cardiac disease and heart failure [30, 31, 53]. Recently, G-protein-coupled BA receptor-1 has been identified as central pathway in BA-mediated hemodynamic alterations [28, 29]. We observed a significant correlation of TC and TCDC with arterial blood pressure in our cohort.…”

Serum bile acids as marker for acute decompensation and acute‐on‐chronic liver failure in patients with non‐cholestatic cirrhosis

“…BAs are directly vasoactive and induce splanchnic vasodilation by relaxing smooth muscle cells and may contribute to portal hypertension . Recently, stimulation of G‐protein‐coupled BA receptor‐1 was described as central pathway for inducing peripheral vasodilation via BAs . Furthermore, BA seem to directly activate inflammatory pathways in hepatocytes during cholestasis by stimulating production of proinflammatory mediators .…”

“…41,43 Recently, stimulation of G-protein-coupled BA receptor-1 was described as central pathway for inducing peripheral vasodilation via BAs. 47,48 Furthermore, BA seem to directly activate inflammatory pathways in hepatocytes during cholestasis by stimulating production of proinflammatory mediators. 49,50 Beside this, BA signalling aspects, via the nuclear receptor FXR as well as TGR5, modulate the whole bodies energy and metabolic regulation.…”

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

“…This results in gallbladder filling and volume expansion, which is a major obstacle in the clinical application of TGR5 agonists. In addition, impaired immune responses [14] and alterations in heart rate have been identified as side effects of TGR5 activation [15,16] . Recent research has demonstrated that TGR5 activation and subsequent GLP-1 secretion occur at the luminal…”