R- and S-terbutaline activate large conductance and Ca 2+ dependent K + (BK Ca ) channel through interacting with β 2 and M receptor respectively

Abstract

This study investigated the effect of the β receptor agonist terbutaline on the single channel activity of BK channel. The effects of racemate and two isomers of terbutaline were all assessed. β adrenoceptors were stably overexpressed on HEK293 cells by lentiviral transduction method and chicken BK channels were transiently expressed on normal HEK293 cell line or HEK293 cells overexpressing β receptors. Data showed that terbutaline significantly increased the single channel open probability of BK channel within 10min. The channel activating effects of terbutaline are stereoselective and mainly stay with the R-enantiomers. The opening probability of BK channel at 10min after drug application normalized to that just before drug application (Po10/Po0s) for R- and S-terbutaline were 7.85±3.20 and 1.06±0.45 respectively at 1μM concentration, corresponding to 28.37±9.96 and 2.68±1.09 at the higher concentration of 10μM. ICI 118551 blocked the effect of R- but not S-terbutaline (10μM), whereas atropine blocked the channel activating effects of S-terbutaline of higher concentration. In addition, the muscarinic receptor agonist carbachol increased the BK channel activity in an atropine-sensitive manner as an positive control experiment, which indicate the involvement of M receptor in the channel activating effect of S-terbutaline.

Ex Vivo Pulmonary Oedema after In Vivo Blast-Induced Rat Lung Injury: Time Dependency, Blast Intensity and Beta-2 Adrenergic Receptor Role

“…β 2 -adrenoceptor agonists via activation of β 2 ARs regulate necessary key proteins for the process of alveolar epithelial active Na + transport through activation and increase in expression of ion channels and reduce pulmonary endothelial permeability [ 31 , 32 , 33 , 34 , 35 , 36 ]. Ion channels which can be modulated by β 2 -adrenoceptor agonists by their activity or expression include epithelial sodium channel (ENaC) [ 21 , 36 , 37 ], Na + /K + -ATPase [ 30 , 38 , 39 , 40 , 41 ], cystic fibrosis transmembrane conductance regulator (CFTR) [ 42 ], cyclic nucleotide-gated cation (CNG) channels [ 21 ], nonselective cation channel (NSCCa) [ 43 ] and Ca 2+ dependent K + channel (BKCa) [ 44 , 45 ]. Moreover, treatment with β2-agonists increases the secretion of surfactant proteins and exerts anti-inflammatory properties by influencing several types of immune cells and reducing fibrotic remodelling [ 16 , 46 ].…”

Enantioselective resolution of Rac‐terbutaline and evaluation of optically pure R‐terbutaline hydrochloride as an efficient anti‐asthmatic drug

“…Previous studies demonstrated that R ‐isomer of TBT was the potent part to generate the activity by stimulating β 2 ‐adrenoceptor, while the S ‐isomer had virtually no affinity for β 2 ‐adrenoceptor or was predominantly ascribable to the side effects, such as causing airway hyperreactivity and cardiac disorders . Recently, Zhuo Fan et al reported that, S ‐enantiomer of TBT may activate muscarinic receptors which could generate the airway hyperreactivity of racemic terbutaline . To date, much efforts have been devoted to produce R ‐TBT 5 , either by absolute asymmetric synthesis, or by chemo‐enzymatic method in which asymmetric reduction of a substituted α ‐chloroacetophenone derivative with cultured whole‐cell biocatalyst of yeast (Williopsis californica JCM 3600), or by catalytic asymmetric synthesis from chloroketones, or using chiral selector (β‐cyclodextrin or its derivatives) .…”

“…[6][7][8][9][10][11] Recently, Zhuo Fan et al reported that, S-enantiomer of TBT may activate muscarinic receptors which could generate the airway hyperreactivity of racemic terbutaline. 12 To date, much efforts have been devoted to produce R-TBT 5, either by absolute asymmetric synthesis, 13 or by chemo-enzymatic method in which asymmetric reduction of a substituted α-chloroacetophenone derivative with cultured wholecell biocatalyst of yeast (Williopsis californica JCM 3600), 14 or by catalytic asymmetric synthesis from chloroketones, 15 or using chiral selector (β-cyclodextrin or its derivatives). [16][17][18][19] However, these methods couldn't achieve products with high optical purity for industrial application.…”