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  • Other membrane currents are affected as

    2020-03-20

    Other membrane currents are affected as well. Some studies have provided evidence that sulfonylureas, in addition to blocking KATP channels, also inhibit chloride and calcium channels. GLYB has been shown to almost inhibit the current generated by Na+–K+ pumps in a concentration-dependent manner (with IC50≈100μM) and to decrease the current through L-type calcium channels in cardiac myocytes [32]. GLYB markedly inhibited cystic fibrosis transmembrane regulator chloride currents in a voltage-independent manner, with IC50 value of 12.5μM at +50mV. The outwardly rectifying swelling-activated Cl− current in atrial Fructose Colorimetric/Fluorometric Assay Kit was less sensitive to GLYB and the block was voltage-dependent [9]. Macroscopic chloride currents that are activated by an increase of intracellular Ca2+ were also markedly inhibited by GLYB in a voltage-independent manner, with IC50≈62μM at +50mV [9]. In our experiments, GLYB inhibited the activity of single chloride channels from vesicles of mitochondrial membranes isolated from rat heart muscle. Half-maximal inhibition of activity (IC50) with the data fitted by a sigmoidal function was achieved at GLYB concentration of 129μM. This value is of the same order as is the IC50 for outwardly rectifying swelling-activated Cl− current in atrial cells (193μM at +50mV) and twice the IC50 for Ca2+-dependent Cl− current [9]. GLYB affected the channels already at concentration range where the activity was not yet decreased at this concentration, in Fig. 3 can be seen the effect on mean open time τopen. The IC50 value for the shortening of τopen is in range of tens of μM GLYB. With only slow changes of mean closed time, this indicates that GLYB might act like an open-channel blocker. This mechanism of action is consistent with the observed decrease of current amplitude. The increase of mean closed time at 500μM concentration of GLYB was also due to the low amplitude of the very short events, thus, many events did not achieve the 50% threshold for the detection of opening. Inhibition by GLYB was reversible, after wash out of GLYB away from solution the activity of chloride channel was fully restored and the open level could be discerned properly again. Open-channel block by GLYB was also observed on both whole-cell current through volume-sensitive outwardly rectifying chloride channels [33] and at single channel level [10], [11]. Our findings could be in line with the work of Ovide-Bordeaux et al., who observed the lack of effect of either GLYB or KATP channel opener – diazoxide in absence of exogenous ATP. In presence of exogenous ATP, 100μM GLYB inhibited ADP-stimulated respiration, an effect which was not connected to the activity of mitochondrial KATP channel because it was not reversed by diazoxide [34]. As they discussed, GLYB might have other targets. One of them seems to be also the mitochondrial chloride channel, whose inhibition was shown to have cardioprotective effect, similarly as the activation of mitochondrial KATP channel [35].
    Acknowledgments The study was supported by Grants VEGA2-0050-13 and VEGA2-0094-12. We thank Dr. Alexandra Zahradnikova for her kindness to use Clampfit 10 software to analyze data.
    Introduction Transport functions in the placenta are of great importance for fetal growth and development. The human placental syncytiotrophoblast is a polarized epithelial structure that constitutes the main barrier to materno-fetal exchange. Ionic transport in the syncytiotrophoblast involves conductive pathways that are associated with numerous epithelial functions, such as maintenance of membrane potential, cell volume regulation and solute transport among others. Chloride (Cl−) is the main anion in the extracellular fluid in the fetus, as it is in the adult, but at all gestational ages fetal Cl− concentration is 5–6mM higher than in maternal blood. There are no maternal–fetal differences in either Na+ or K+ concentrations [1]. Chloride exchange between mother and fetus in the placenta occurs via multiple pathways; because the hSTB is a syncytium, chloride must pass directly through both trophoblast membranes. As with intestinal mucosa and the renal epithelium, in hSTB the pathways for chloride transport could be passive or active, depending on placental permeability and electrochemical potential differences for the ion. Initially, there was considerable interest focused on Cl− conductances in the hSTB membranes and their regulation. However, the identities of the specific ion channels underlying these conductances, including which are involved in the different placental processes, are still unknown. Recently, new evidence has emerged supporting the relationship between specific types of chloride channels and particular functions. For instance, a DIDS-sensitive conductance contributes to the resting potential of the syncytiotrophoblast microvillous membrane and is involved in volume regulation [2]. There is also strong evidence that the apical Maxi-chloride channel, a channel sensitive to DIDS, is permeable to organic anions like taurine, glutamate and aspartate. These characteristics suggest that this channel could play a role in phenomena such as volume regulation and taurine transport [3]. The biophysical characteristics of this Maxi-chloride channel are altered in preeclampsia [4], however, the consequences of this alteration for volume regulation and taurine transport in preeclampsia are open questions.