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The Arctic zone of the Russian Federation is one of the most intensively developing regions of the country. Amongst the major domains of economic and industrial growth and improvement is transport infrastructure and particularly the railway network. This area is being exposed to negative factors of rapid climate change that can significantly affect and compromise this activity. Thus, it is vital to take them into account during design, construction, and operation of the railway infrastructure facilities. This work details the production of a digital atlas comprising the 1950–2021 dynamics of the main hydrometeorological parameters: air and soil temperature, precipitation, wind speed, air and soil humidity, and snow cover thickness. The maps are based on climatic data derived from the MERRA-2 (Modern-Era Retrospective Analysis for Research and Applications, version 2) reanalysis. In total there are 459, which are arranged into 7 chapters. The atlas geographically covers the western part of the Russian Arctic encompassing the regions of quite intensive transport development, which includes the construction of the Northern Latitudinal Railway. Original algorithms of geospatial data processing and their further representation as well as the maps compiled in GIS environment are discussed. Comprehensive analysis of climatic changes in the region of the Russian Arctic including detailed quantitative evaluation over 40 years is given. In the Discussion, we focus on those changes of the regional climate which, from our point of view, are the most significant for consideration by railway operators. The obtained results contribute to framing the theoretical basis of design, development, and sustainable operation of the railway infrastructure in the Arctic and facilitate the decision-making process. This is the first experience of building a specialized climatic cartographic product for the needs of the Russian railways, and to our knowledge the first atlas such as that in the world. In the future, the amassed experience may be transferred to other regions of the Russian Federation as well as similar regions in Canada, Sweden and Highland China that are also subject to significant climate change.

Citrulline is a non-proteinogenic amino acid that forms as by-product in nitric oxide (NO) synthesis from arginine and may act in concert with NO as an independent signaling molecule that involves in the mechanism of vascular smooth muscle vasodilation. In this study we examined the effects of citrulline on pulmonary artery smooth muscles. Experimental design comprised outward potassium currents measurements in enzymatically isolated rat pulmonary artery smooth muscle (PASMc) cells using whole-cell patch clamp technique, isometric contractile force recordings on rat pulmonary artery rings and method of molecular docking simulation. Citrulline in a concentration 10 -9 -10 -5 M relaxed phenylephrine (PHE)-preactivated SM of rat pulmonary artery in a dose-dependent manner (EC 50 0,67 μM). This citrulline-induced relaxation was dependent on an intact endothelium. Bath application of citrulline (10 -8 -10 -5 M) on isolated PASMc induced a significant increase in the amplitude of outward potassium current (I k ). The adenosine antagonist caffeine (10 -6 M) effectively blocked both the citrulline-induced relaxation response and I k increment. Molecular docking modeling suggests that caffeine blocking the potent activity of citrulline results from competitive interactions at the A 2 adenosine receptor binding site. In summary, our data suggest that citrulline, released with NO at low concentrations, can effectively interact with adenosine receptors in smooth muscle cells, causing their relaxation, indicating surprising interaction between NO and adenosine pathways., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Our scientific interest lies in the pharmacology, physiology and biophysics of vascular smooth muscle under extreme conditions and in vascular pathology (hypoxia, ionizing radiation, diabetes, arterial hypertension)]., (Copyright © 2024. Published by Elsevier Inc.)

Oxidative stress results from the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in quantities exceeding the potential activity of the body's antioxidant system and is one of the risk factors for the development of vascular dysfunction in diabetes and exposure to ionizing radiation. Being the secondary products of normal aerobic metabolism in living organisms, ROS and RNS act as signaling molecules that play an important role in the regulation of vital organism functions. Meanwhile, in high concentrations, these compounds are toxic and disrupt various metabolic pathways. The various stress factors (hyperglycemia, gamma-irradiation, etc.) trigger free oxygen and nitrogen radicals accumulation in cells that are capable to damage almost all cellular components including ion channels and transporters such as Na + /K + -ATPase, BK Ca , and TRP channels. Vascular dysfunctions are governed by interaction of ROS and RNS. For example, the reaction of ROS with NO produces peroxynitrite (ONOO - ), which not only oxidizes DNA, cellular proteins, and lipids, but also disrupts important signaling pathways that regulate the cation channel functions in the vascular endothelium. Further increasing in ROS levels and formation of ONOO - leads to reduced NO bioavailability and causes endothelial dysfunction. Thus, imbalance of ROS and RNS and their affect on membrane ion channels plays an important role in the pathogenesis of vascular dysfunction associated with various disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Gold nanoparticles are widely used for biomedical applications, but the precise molecular mechanism of their interaction with cellular structures is still unclear. Assuming that intracellular calcium fluctuations associated with surface plasmon-induced calcium entry could modulate the activity of potassium channels, we studied the effect of 5 nm gold nanoparticles on calcium-dependent potassium channels and associated calcium signaling in freshly isolated rat pulmonary artery smooth muscle cells and cultured hippocampal neurons., Methods: Outward potassium currents were recorded using patch-clamp techniques. Changes in intracellular calcium concentration were measured using the high affinity Ca 2+ fluorescent indicator fluo-3 and laser confocal microscope., Results: In pulmonary artery smooth muscle cells, plasmonic gold nanoparticles increased the amplitude of currents via large-conductance Ca 2+ -activated potassium channels, which was potentiated by green laser irradiation near plasmon resonance wavelength (532 nm). Buffering of intracellular free calcium with ethylene glycol-bis-N,N,N',N'-tetraacetic acid (EGTA) abolished these effects. Furthermore, using confocal laser microscopy it was found that application of gold nanoparticles caused oscillations of intracellular calcium concentration that were decreasing in amplitude with time. In cultured hippocampal neurons gold nanoparticles inhibited the effect of EGTA slowing down the decline of the BK Ca current while partially restoring the amplitude of the slow after hyperpolarizing currents., Conclusion: We conclude that fluctuations in intracellular calcium can modulate plasmonic gold nanoparticles-induced gating of BK Ca channels in smooth muscle cells and neurons through an indirect mechanism, probably involving the interaction of plasmon resonance with calcium-permeable ion channels, which leads to a change in intracellular calcium level., (© 2023 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Hypoxic pulmonary vasoconstriction (HPV) is the most important feature of intact lung circulation that matches local blood perfusion to ventilation. The main goal of this work was to study the effects of diabetes on the development of HPV in rats. The experimental design comprised diabetes mellitus induction by streptozotocin, video-morphometric measurements of the lumen area of intrapulmonary arteries (iPAs) using perfused lung tissue slices and patch-clamp techniques. It was shown that iPA lumen size was significantly reduced under physical and chemical hypoxia (7-10 mm Hg) in normal iPA, but, on the contrary, it clearly increased in diabetic lung slices. The amplitude of the outward K + current in diabetic iPAs smooth muscle cells (SMCs) was two-fold greater than that seen in healthy cells. Chemical hypoxia led to significant decrease in the amplitude of the K + outward current in healthy iPA SMCs while it was without effect in diabetic cells. The data obtained clearly indicate a significant dysregulation of vascular tone in pulmonary circulation under diabetes, ie diabetes damages the adaptive mechanism for regulating blood flow from poorly ventilated to better ventilated regions of the lung under hypoxia. This effect could be clinically important for patients with diabetes who have acute or chronic lung diseases associated with the lack of blood oxygenation., (© 2019 John Wiley & Sons Australia, Ltd.)

Colloidal gold nanoparticles (AuNPs) of ~5nm core size and Zeta-potential of -35mV, having absorption maximum and plasmon resonance in the range of 510-570nm, were studied as a potential K(+)-channel opener in vascular smooth muscle (SM) cells. Experimental design of the study comprised SM contractile recordings. When externally applied to the organ bath, AuNPs (10(-6)-3×10(-4)M) led to decrease in amplitude of norepinephrine-induced contractions in a concentration-dependent and endothelium-independent manner in SM thoracic aorta, with mean value of pD2 (-log EC50) 4.2±0.03, Emax=55±4%. Being added to the bath solution in concentration of 10(-4)M, AuNPs significantly increased whole cell peak outward current at +70mV from 32±2pA/pF to 59±5pA/pF (n=14, P<0.05). External irradiation using a 5mW/532nm green laser, to facilitate plasmon resonance, led to an increment in the AuNPs-induced macroscopic outward potassium current (IK) from 59±5pA/pF to 74±1pA/pF (n=10, P<0.05). Paxilline (500nM), when added to the external bathing solution, significantly decreased AuNPs-induced increment of IK in SM cells. Single channel recordings provided a direct confirmation of BKCa activation by AuNPs at the single-channel level. Application of AuNPs to the bath potentiated BKCa activity with a delay of 1-2min, as was seen initially by more frequent channel openings followed by the progressive appearance of additional open levels corresponding to multiple openings of channels with identical single-channel amplitudes. Eventually, after 10-15min in the presence of AuNPs and especially when combined with the green laser illumination, there was a massive increase in channel activity with >10 channels evident. When irradiated by laser, AuNPs significantly increased the amplitude of maximal AuNPs-induced relaxation from 55±5% to 85±5% (n=10, P<0.05) while the sensitivity of SM to AuNPs was without changes. In summary, plasmonic AuNPs possess the ability to activate BKCa channel opening in vascular SM. Laser irradiation facilitates this effect due to local plasmon resonance that, in turn, further increases BKCa channel activity causing SM relaxation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Abstract Background: Endothelium and K+ channel functionality in smooth muscle cells (SMCs) regulates vascular function and is exposed to damage in diabetes. The regulatory enzyme protein kinase C (PKC) is known to play a key role in vascular tone regulation in health and disease. In this study, we evaluated the effect of PKC-δ gene silencing using small interfering RNAs (siRNAs) on endothelial dysfunction and acquired potassium channelopathy in vascular SMCs in diabetes. Methods: The experimental design comprised diabetes induction by streptozotocin (65 mg/kg) in rats, RNA interference, isolated aortic ring contractile recordings, whole-cell patch-clamp technique, measurements of reactive oxygen species (ROS), and real-time polymerase chain reaction technique. Animals were killed by cervical dislocation following ketamine (45 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.) anesthesia administration on the third month of diabetes and on the seventh day after intravenous injection of siRNAs. Results: The aortas of diabetic rats demonstrated depressed endothelium-dependent relaxation and integral SMCs outward K+ currents as compared with those of controls. On the seventh day, PKC-δ gene silencing effectively restored K+ currents and increased the amplitude of vascular relaxation up to control levels. An increased level of PKC-δ mRNA in diabetic aortas appeared to be reduced after targeted PKC-δ gene silencing. Similarly, the level of ROS production that was increased in diabetes came back to control values after siRNAs administration. Conclusions: The silencing of PKC-δ gene expression using siRNAs led to restoration of vasodilator potential in rats with diabetes mellitus. It is likely that the siRNA technique can be a good therapeutic tool to normalize vascular function in diabetes.

Potassium conductance in vascular smooth muscle (VSM) is known to be altered in arterial hypertension. High level of protein kinase C (PKC) activity is a common feature for hypertension of different genesis. The main goal of this study was to investigate the efficacy of the RNA interference (RNAi) technique targeting PKC delta-isoform gene as a possible pharmacological tool to restore vasodilator potential in spontaneously hypertensive rats (SHR). Experimental design of the study comprised RNAi and patch-clamp techniques, RT-PCR analysis and standard acetylcholine test. Total outward currents and acetylcholine-induced endothelium-dependent relaxant responses were blunted in SHR. BKCa alpha subunit mRNA expression in SHR was unchanged whereas KV and KATP mRNA expression appeared significantly increased. PKC inhibitor, chelerythrine (100 nM), restored potassium channels activity in SHR. PKC-delta-isoform protein expression and PKC-delta-isoform mRNA expression are 2.5-4 fold increased in VSM from SHR. PKC gene silencing with the short hairpin RNAs (shRNAs)-plasmid delivery system administered intravenously led to an increment in maximal amplitude of acetylcholine-relaxation, restored outward K(+) currents and PKC-delta-isoform mRNA and protein expression. Arterial blood pressure in SHR was normalized following shRNAs administration. We conclude that BKCa channels are likely to be the most PKC-dependent member of K(+) channels family responsible for vascular hypercontractility in SHR while Kv and KATP channels may constitute a reserve mechanism for the maintenance of vasodilator potential under BKCa channelopathy. It is likely that RNAi technique is a good therapeutic approach to inactivate PKC gene and to normalize vascular functions and high arterial blood pressure in SHR., (© 2013 Published by Elsevier B.V.)

It is likely that large-conductance Ca²⁺-activated K⁺ (BK(Ca)) channels channelopathy tightly involved in vascular malfunctions and arterial hypertension development. In the present study, we compared the results of siRNAs-induced α-BK(Ca) gene silencing and vascular abnormalities produced by whole-body ionized irradiation in rats. The experimental design comprised RT-PCR and patch clamp technique, thoracic aorta smooth muscle (SM) contractile recordings and arterial blood pressure (BP) measurements on the 30th day after whole body irradiation (6Gy) and following siRNAs KCNMA1 gene silencing in vivo. The expression profile of BK(Ca) mRNA transcripts in SM was significantly decreased in siRNAs-treated rats in a manner similar to irradiated SM. In contrast, the mRNA levels of K(v) and K(ATP) were significantly increased while L-type calcium channels mRNA transcripts demonstrated tendency to increment. The SMCs obtained from irradiated animals and after KCNMA1 gene silencing showed a significant decrease in total K⁺ current density amplitude. Paxilline (500 nM)-sensitive components of outward current were significantly decreased in both irradiated and gene silencing SMCs. KCNMA1 gene silencing increased SM sensitivity to norepinephrine while Ach-induced relaxation had decreased. The silencing of KCNMA1 had no significant effect on BP while radiation produced sustained arterial hypertension. Therefore, radiation alters the form and function of the BK(Ca) channel and this type of channelopathy may contribute to related vascular abnormalities. Nevertheless, it is unlikely that BK(Ca) can operate as a crucial factor for radiation-induced arterial hypertension., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The effect of intravenous administration of human mesenchymal stromal stem cells (hMSC) has been evaluated by means of large-conductance calcium-dependent potassium channel (BK(Ca)) activity measurements in thoracic aorta smooth muscle cells (SMC) obtained from non-fatal whole-body irradiated rats, using the patch clamp technique in whole-cell modification, and the standard acetylcholine (ACh) test to evaluate functional endothelium integrity using SM contractile recordings. Myofilament calcium sensitivity was estimated using simultaneous contractile recordings versus [Ca(2+)](i). Arterial blood was measured in intact and irradiated rats before and after hMSC administration. Stimulation of isolated SMC from the control group of animals with depolarizing voltage steps showed that outward K(+) currents sensitive to the BK(Ca) inhibitor paxilline were expressed. Outward currents in SMC obtained from irradiated animals were significantly reduced on the 30th day of post-irradiation. Irradiation led to a significant elevation in arterial blood pressure and reduced ACh-induced relaxation responses in irradiated rats as compared with the control group. Simultaneous measurements of contractile force and [Ca(2+)](i) showed that myofilament Ca(2+) sensitivity had increased following irradiation. Intravenously injected hMSC effectively restored BK(Ca) current and the amplitude of ACh-induced endothelium-dependent vasodilatation in vascular tissues obtained from post-irradiated rats. SMC obtained from irradiated rats treated with hMSC demonstrated a significantly increased paxilline-sensitive component of outward potassium currents, indicating that BK(Ca) activity had been restored. hMSC administration normalized increased blood pressure and myofilament Ca(2+) sensitivity in irradiated animals. When administered to healthy rats, hMSC were without effects on either of these. This study does not provide any immunohistochemical proof of hMSC engraftment in the host rats. PCR analysis showed that hMSCs were negative for hematopoietic cell markers and positive for hMSC markers. There were no clinical signs of graft-versus-host disease throughout the experimental period of 30 days. The data obtained suggest that hMSC demonstrate a clearly expressed ability to normalize vascular function damaged following irradiation, i.e. to reduce an elevated arterial blood pressure and myofilament Ca(2+) sensitivity, and to repair BK(Ca) function and endothelium-dependent relaxation in vascular tissues obtained from irradiated animals. Thus, hMSC seem to be worthwhile therapeutic approach in cases of ionizing irradiation accident or radiation beam therapy.

The goal of the present study was to investigate the effects of quercetin-filled phosphatidylcholine liposomes (PCL-Q) on the currents carried by large conductance Ca(2+)-dependent K(+) channels (BK(Ca)) in rat thoracic aorta following non-fatal whole-body ionizing irradiation. Using patch-clamp technique, it is found that the outward K(+) currents of isolated smooth muscle cells (SMCs) stimulated by depolarizing voltage steps were sensitive to BK(Ca) inhibitor, paxilline, and this kind of outward K(+) currents in SMCs from irradiated animals demonstrated a significant decrease in amplitude. Radiation-induced BK(Ca) suppression was evident 9 days post-irradiation and progressively increased over 30 days of experimental period. Thus, the vasorelaxing force of these SMCs may be diminished following irradiation. PCL-Q effectively restored BK(Ca) function in post-irradiated SMCs. It is noteworthy that the constituents of PCL-Q, i.e., free quercetin (Q) and "empty" liposomes (PCL), being taken separately, showed a decreased ability to recover BK(Ca) function as compared with combined composition. These results suggest that PCL-Q is able to regain normal function of BK(Ca) following irradiation. The protective effects of PCL-Q can be explained by its antioxidant and membrane repairing properties as well as its ability to inhibit protein kinase C activity. Thus, the lipid encapsulation of flavonoid, PCL-Q, appears to be a potential medication in the case of ionizing irradiation accident, and for the patients with neoplasm who have to receive external radiotherapy as well.

Aims: The goal of this study was to evaluate the influence of gamma-irradiation on Ca(2+)-activated K(+) channel (BK(Ca)) function and expression in rat thoracic aorta., Main Methods: Aortic cells or tissues were studied by the measurement of force versus [Ca(2+)](i), patch-clamp technique, and RT-PCR., Key Findings: Stimulation of smooth muscle cells with depolarizing voltage steps showed expression of outward K(+) currents. Paxilline, an inhibitor of BK(Ca) channels, decreased outward K(+) current density. Outward currents in smooth muscle cells obtained from irradiated animals 9 and 30 days following radiation exposure demonstrated a significant decrease in K(+) current density. Paxilline decreased K(+) current in cells obtained 9 days, but was without effect 30 days after irradiation suggesting the absence of BK(Ca) channels. Aortic tissue from irradiated animals showed progressively enhanced contractile responses to phenylephrine in the post-irradiation period of 9 and 30 days. The concomitant Ca(2+) transients were significantly smaller, as compared to tissues from control animals, 9 days following irradiation but were increased above control levels 30 days following irradiation. Irradiation produced a decrease in BK(Ca) alpha- and beta(1)-subunit mRNA levels in aortic smooth muscle cells suggesting that the vasorelaxant effect of these channels may be diminished., Significance: These results suggest that the enhanced contractility of vascular tissue from animals exposed to radiation may result from an increase in myofilament Ca(2+) sensitivity in the early post-irradiation period and a decrease in BK(Ca) channel expression in the late post-irradiation period.