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Using density functional theory at D3‐B3LYP/aug‐cc‐pVDZ level combined with the conductor‐like polarizable continuum model (CPCM) solvent model, a study of the IR spectrum of H2O:HCN mixtures is reported. The CPCM solvent effect notably enhances the accuracy of the IR spectra compared to gas‐phase calculations, while the dielectric constant value has minimum impact on the final spectrum. An optimized methodology is suggested that effectively minimizes the root mean square deviation between theoretical and experimental data. This novel approach not only enhances the quality of the final IR spectra but also captures relevant spectral features, highlighting its potential to decipher molecular interactions in such intricate mixtures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fruit flies are important economic pests of fruits, vegetables, and nuts all over the world. In this study, a permanent ecological trap, which was created by the ovicidal effect of phytogenic hydrogen cyanide (HCN) liberated from passion fruits due to oviposition by fruit flies and can be used in the pest management, were determined. RESULTS: Observation of fruit fly eggs in Passiflora within the passion fruit cultivation region in southern China, from Aug 2019 to Oct 2020 showed that the exotic Passiflora attracted the native fruit flies to oviposit, but the eggs could not hatch. Using classical staging to categorize embryonic development and fumigation assays, we show that oviposition by fruit fly on passion fruits, release HCN from the cyanogenic mesocarp. Exposure of the eggs to HCN causes arrest of embryonic development and finally the death of eggs. CONCLUSION: Our results reveal that the life cycle of fruit fly in Passiflora is interrupted at the egg stage. Consequently, we predict that this ecological trap may be permanent. Extensive cultivation of the Passiflora vine as a dead‐end trap crop may be an effective avenue to reduce populations of fruit fly pests. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The process of recycling flue gas to the boiler of a pressurized oxy‐combustion system could affect the final concentration of NOx, which is very important for an appropriate design of the carbon capture process. During the recycling process, HCN, as the main intermediate of the reburn reaction, may interact with NO significantly to determine the final NO emissions. The current study aims to assess the gas‐phase interactions of HCN and NO in a CO2 atmosphere, which is customary to pressurized oxy‐combustion conditions. A kinetic modeling study of the oxidation of HCN in the presence of NO has been performed under POC conditions and in the 973–1473 K temperature range. The influences of the stoichiometry, pressure, H2O concentration, and NO inlet concentration are analyzed. The results show that the HCN–NO interaction reduces both HCN and NO and that the interaction increases as pressure increases when the temperature is above 1073 K, whereas the opposite is found in low‐temperature regions. The effect of stoichiometric parameters also strongly depends on temperature but follows the opposite trend compared with the effect of pressure. These differences contribute to the suppressive effect on O2 decomposition and the positive effect on H2O decomposition at elevated pressures. An optimal temperature for NO reduction is shifted to lower temperature with increasing pressure and H2O concentration. The analysis of the total fixed nitrogen (TFN) indicates that for an actual boiler (5% O2), the temperature should be controlled at 1373, 1223, 1173, and 1173 K, respectively, as the pressure increases from 1 to 15 atm. Finally, a 21‐species and 69‐step reduced chemistry is developed and validated to accurately predict the interaction of HCN with NO at elevated pressures. [ABSTRACT FROM AUTHOR]

Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are members of the voltage‐gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel‐blocker, is FDA‐approved for clinical use as a heart rate‐reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient‐derived tumour xenograft models established from triple‐negative breast cancer (TNBC) tissues, with no evident side‐effects on the mice. Transcriptome‐wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER‐stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER‐stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER‐stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy. [ABSTRACT FROM AUTHOR]

Aim: Acetylcholine release is vital in the pacing of theta rhythms in the hippocampus. The subiculum is the output region of the hippocampus with different neuronal subtypes that generate theta oscillations during arousal and rapid eye movement sleep. The combination of intrinsic resonance in the hippocampal neurons and the periodic excitation of hippocampal excitatory and inhibitory neurons by cholinergic pathway drives theta oscillations. However, the acetylcholine mediated effect on intrinsic subthreshold resonance generating hyperpolarization‐activated cyclic nucleotide‐gated current, Ih of subicular neurons is unexplored. We studied the acetylcholine receptor‐independent effect of cholinergic agents on the intrinsic properties of subiculum principal neurons and the underlying mechanism. Methods: We bath perfused acetylcholine or nicotine on rat brain slices in the presence of synaptic blockers. The physiological effect was studied by cholinergic fibres stimulation and electrophysiological recordings under whole‐cell mode of subiculum neurons using septohippocampal sections. Results: Exogenously applied acetylcholine in the presence of atropine affected two groups of subicular neurons differently. Acetylcholine reduced the resonance frequency and Ih in bursting neurons, whereas these properties were unaffected in regular firing neurons. Subsequently, the endogenously released acetylcholine by stimulation showed a selective suppressive effect on Ih, sag, and resonance in burst firing among the two excitatory neurons. Nicotine suppressed the Ih amplitude in burst firing neurons, which was evident by decreased sag amplitude and resonance frequency and increased excitability. Conclusion: Our study suggests cell type‐specific acetylcholine receptor‐independent shift in resonance frequency by partially inhibiting HCN current during high cholinergic inputs. [ABSTRACT FROM AUTHOR]

The spatial and temporal balance of spinal α‐motoneuron (αMN) intrinsic membrane conductances underlies the neural output of the final common pathway for motor commands. Although the complete set and precise localization of αMN K+ channels and their respective outward conductances remain unsettled, important K+ channel subtypes have now been documented, including Kv1, Kv2, Kv7, TASK, HCN and SK isoforms. Unique kinetics and gating parameters allow these channels to differentially shape and/or modify αMN firing properties, and recent immunohistochemical localization of K+‐channel complexes reveals a framework in which their spatial distribution and/or focal clustering within different surface membrane compartments is highly tuned to their physiological function. Moreover, highly evolved regulatory mechanisms enable specific channels to operate over variable levels of αMN activity and contribute to either state‐dependent enhancement or diminution of firing. While recent data suggest an additional, non‐conducting role for clustered Kv2.1 channels in the formation of endoplasmic reticulum–plasma membrane junctions postsynaptic to C‐bouton synapses, electrophysiological evidence demonstrates that conducting Kv2.1 channels effectively regulate αMN firing, especially during periods of high activity in which the cholinergic C‐boutons are engaged. Intense αMN activity or cell injury rapidly disrupts the clustered organization of Kv2.1 channels in αMNs and further impacts their physiological role. Thus, αMN K+ channels play a critical regulatory role in motor processing and are potential therapeutic targets for diseases affecting αMN excitability and motor output, including amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

The hippocampus is an extended structure displaying heterogeneous anatomical cell layers along its dorsoventral axis. It is known that dorsal and ventral regions show different integrity when it comes to functionality, innervation, gene expression, and pyramidal cell properties. Still, whether hippocampal interneurons exhibit different properties along the dorsoventral axis is not known. Here, we report electrophysiological properties of dorsal and ventral oriens lacunosum moleculare (OLM) cells from coronal sections of the Chrna2‐cre mouse line. We found dorsal OLM cells to exhibit a significantly more depolarized resting membrane potential compared to ventral OLM cells, while action potential properties were similar between the two groups. We found ventral OLM cells to show a higher initial firing frequency in response to depolarizing current injections but also to exhibit a higher spike‐frequency adaptation than dorsal OLM cells. Additionally, dorsal OLM cells displayed large membrane sags in response to negative current injections correlating with our results showing that dorsal OLM cells have more hyperpolarization‐activated current (Ih) compared to ventral OLM cells. Immunohistochemical examination indicates the h‐current to correspond to hyperpolarization‐activated cyclic nucleotide‐gated subunit 2 (HCN2) channels. Computational studies suggest that Ih in OLM cells is essential for theta oscillations in hippocampal circuits, and here we found dorsal OLM cells to present a higher membrane resonance frequency than ventral OLM cells. Thus, our results highlight regional differences in membrane properties between dorsal and ventral OLM cells allowing this interneuron to differently participate in the generation of hippocampal theta rhythms depending on spatial location along the dorsoventral axis of the hippocampus. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase activating polypeptide (PACAP), acting through its cognate receptors PAC1, VPAC1, and VPAC2, is a pleiotropic signaling neuropeptide of the vasoactive intestinal peptide/secretin/glucagon family. PACAP has known functions in neuronal growth, development, and repair, and central PACAP signaling has acute behavioral consequences. One of the ways in which PACAP may affect neuronal function is through the modulation of intrinsic membrane currents to control neuronal excitability. Here, we review the evidence of PACAP‐dependent modulation of calcium‐ and voltage‐gated potassium currents, hyperpolarization‐activated cation currents, calcium currents, and voltage‐gated sodium currents. Interestingly, PACAP signaling pathways diverge into parallel pathways to target different ionic currents for modulation, though single pathways are not limited to modulating just one target ionic current. Despite the various targets of modulation, the weight of the evidence suggests that PACAP signaling most commonly leads to a net increase in neuronal excitability. We discuss possible mechanisms by which PACAP signaling leads to the modulation of intrinsic membrane currents that may contribute to changes in behavior. [ABSTRACT FROM AUTHOR]

The hyperpolarization‐activated cyclic‐nucleotide‐gated (HCN) ion channels control nerve impulse transmission and cardiac pacemaker activity. The modulation by cAMP is critical for the regulatory function of HCN in both neurons and cardiomyocytes, but the underlying mechanism is not fully understood. Here, we show how the structure of the apo cAMP‐binding domain of the HCN4 isoform has contributed to a model for the cAMP‐dependent modulation of the HCN ion‐channel. This model recapitulates the structural and dynamical changes that occur along the thermodynamic cycle arising from the coupling of cAMP‐binding and HCN self‐association equilibria. The proposed model addresses some of the questions previously open about the auto‐inhibition of HCN and its cAMP‐induced activation, while opening new opportunities for selectively targeting HCN through allosteric ligands. A remaining challenge is the investigation of HCN dimers and their regulatory role. Overcoming this challenge will require the integration of crystallography, cryo electron microscopy, NMR, electrophysiology and simulations. [ABSTRACT FROM AUTHOR]

Abstract: Major impact events have shaped the Earth as we know it. The Late Heavy Bombardment is of particular interest because it immediately precedes the first evidence of life. The reentry of impact ejecta creates numerous chemical by‐products, including biotic precursors such as HCN. This work examines the production of HCN during the Late Heavy Bombardment in more detail. We stochastically simulate the range of impacts on the early Earth and use models developed from existing studies to predict the corresponding ejecta properties. Using multiphase flow methods and finite‐rate equilibrium chemistry, we then find the HCN production due to the resulting atmospheric heating. We use Direct Simulation Monte Carlo to develop a correction factor to account for increased yields due to thermochemical nonequilibrium. We then model 1‐D atmospheric turbulent diffusion to find the time accurate transport of HCN to lower altitudes and ultimately surface water. Existing works estimate the necessary HCN molarity threshold to promote polymerization that is 0.01 M. For a mixing depth of 100 m, we find that the Late Heavy Bombardment will produce at least one impact event above this threshold with probability 24.1% for an oxidized atmosphere and 56.3% for a partially reduced atmosphere. For a mixing depth of 10 m, the probability is 79.5% for an oxidized atmosphere and 96.9% for a partially reduced atmosphere. Therefore, Late Heavy Bombardment impact ejecta is likely an HCN source sufficient for polymerization in shallow bodies of water, particularly if the atmosphere were in a partially reduced state. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects on spontaneous beating rate of mouse atrial preparations following selective block of cardiac 'funny' (f) channels, I(f), and/or suppression of sarcoplasmic reticulum ( SR) function in the absence and presence of β-adrenoceptor stimulation. ZD7288 [to block I(f)] caused a substantial reduction (222 ± 13 bpm) in beating rate from 431 ± 14 to 209 ± 14 bpm, ryanodine alone (to block SR Ca2+ release) reduced beating rate by 105 ± 11 bpm, with subsequent addition of ZD7288 further reducing rate by 57 ± 9 bpm. Cyclopiazonic acid ( CPA) alone (to inhibit Ca2+ reuptake by the SR) reduced beating rate by 148 ± 13 bpm with subsequent addition of ZD7288 further reducing rate by 79 ± 12 bpm. In additional experiments measuring Ca2+ transients in the SA node region using Rhod-2, effects of ivabradine and ZD7288 on rate were again substantially reduced after CPA. Effects of CPA alone on rate developed much more slowly than effects on Ca2+ transient amplitude. ZD7288, ivabradine, and CPA reduced the slope and maximum response of the log(concentration)-response curves for effects of isoprenaline on beating rate. Very little response to isoprenaline remained after treatment with CPA followed by ZD7288. Similar changes in isoprenaline log(concentration)-response curves were seen in guinea pig preparations. These observations are consistent with a role for Ca2+ released from the SR in regulating I(f) and therefore beating rate of SA node preparations; there appear to be additional contributions of SR-derived Ca2+ to effects of β-adrenoceptor stimulation on beating rate that are independent of I(f). [ABSTRACT FROM AUTHOR]

The burnet moth Zygaena filipendulae L. contains the cyanogenic glucosides linamarin and lotaustralin, which can be degraded to the volatiles hydrogen cyanide (HCN), acetone and 2-butanone. Linamarin and lotaustralin are transferred from the male to female duringmating and thus are considered to be involved in mating communication. Because volatile semiochemical cues play a major role in mating communication in many insect species, the emissions of HCN, acetone and 2-butanone from Z. filipendulae are characterized in the present study, aiming to determine the interplay between the degradation products of cyanogenic glucosides and pheromones. The volatile emissions from Z. filipendulae and flowers inducing mating are measured using headspace solid-phase micro-extraction and gas chromatography-mass spectrometry analysis. All Z. filipendulae life stages emit HCN, acetone and 2-butanone. Virgin females show higher emissions than mated females, whereas mated males have higher emissions than virgin males. Hydrogen cyanide is only rarely detected in the course of male-female copulation. These observations indicate a role for the cyanogenic glucoside derived volatiles in female calling and male courtship behaviours, although not as a defence during copulation. Males rejected for mating by a female are accepted after injection of linamarin or lotaustralin, demonstrating that cyanogenic glucosides are also important for female assessment of the fitness of the male. Volatiles from flowers occupied during mate calling are also analyzed, and emissions from males and females result in the identification of novel putative pheromones for Z. filipendulae. [ABSTRACT FROM AUTHOR]

To reduce tyre/road noise, the concept of poroelastic road surfaces (PERS) was invented. PERS is a road surface material that is porous, and at the same time, it is flexible because of the substantial amount of rubber granulate content (from 20% to 85%). The rubber and stone particles are bound by polyurethane resin instead of bitumen. It was feared that in case of fire, because of the high content of rubber and polyurethane, there may be considerable emission of potentially hazardous substances (such as hydrogen cyanide) from burning PERS. Tests performed by the Technical University of Gdansk show that the emission of toxic gases is rather small and that the surface does not promote car fire, even when soaked with fuel. Car fire with fuel spill on PERS is less dangerous for passengers than car fire on dense road surface as the fire is spreading much slower. The article presents results of laboratory and road experiments carried out within FP7 'PERSUADE'. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Cyanogenic glucosides are common bioactive products that break down to release toxic hydrogen cyanide (HCN) when combined with specific β-glucosidases. In forage sorghum, high concentrations of the cyanogenic glucoside dhurrin lead to reduced productivity and sometimes death of grazing animals, especially in times of drought, when the dhurrin content of stunted crops is often higher. The aim of this study was to develop harvesting protocols suitable for sampling in remote areas. Results: Dhurrin concentration in air- and oven-dried leaves was the same as in fresh leaves, with no subsequent losses during storage. Dhurrin concentration was halved when leaves were freeze-dried, although activity of the endogenous dhurrinase was preserved. Direct measurement of dhurrin concentration in methanolic extracts using liquid chromatography/mass spectrometry (LC/MS) gave similar results to methods that captured evolved cyanide. A single freezing event was as effective as fine grinding in facilitating complete conversion of dhurrin to cyanide. Conclusion: Direct measurement of dhurrin using LC/MS is accurate but expensive and not appropriate for fieldwork. Air drying provides an accurate, low-cost method for preparing tissue for dhurrin analysis, so long as the specific β-glucosidase is added. It is recommended that comparative studies like the one presented here be extended to other cyanogenic species. Copyright © 2012 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

1. Plant defence theory predicts trade-offs among defence traits as a result of resource limitation or pleiotropic effects. Although theoretically widely accepted, empirical demonstrations of such trade-offs are surprisingly scarce and mechanistic explanations are usually lacking. 2. We quantified cyanogenesis (the release of hydrogen cyanide (HCN)) as a direct defence and the emission of volatile organic compounds (VOCs) as an indirect defence against herbivores. To elucidate whether the trade-offs occur at the genetic or phenotypic level we investigated cultivated and wild-type accessions of lima bean (Fabaceae: Phaseolus lunatus L.) and compared different leaf developmental stages. Genetic relationships among the accessions were studied using amplified fragment length polymorphism (AFLP) analysis. 3. Cyanogenesis and the release of VOCs differed significantly among the accessions and were negatively correlated: high cyanogenic accessions released low amounts of VOCs and vice versa. The same remained true for the ontogenetic stages, since primary leaves of all accessions hardly ever produced HCN at all, yet regularly showed high release rates of VOCs. 4. Low and high cyanogenic accessions of lima bean formed distinct clades in an AFLP-based dendrogram, while wild-types and cultivars did not separate. The first pattern indicates that the underlying defensive syndromes are genetically conserved, while the latter is likely to be caused by a multiple origin of cultivated lima beans or an extensive gene flow among cultivated and wild plants. 5. Synthesis. Trade-offs between cynogenesis and VOC release were obvious both between accessions and at the ontogenetic level, and thus cannot be explained by pleiotropy. We contend that allocation restrictions and/or adaptations to different enemy pressures are most likely to explain why lima bean can invest into cyanogenesis or VOCs, but not both. [ABSTRACT FROM AUTHOR]

Introduction: It has been speculated that pacemaker current (I f) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I f inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I f in atrial myocytes. Methods and Results: Using patch-clamp technique, we studied effects of ivabradine on I f present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I f inhibition with an IC50 at steady state of 2.9 μM. Time constant of block development (Tauon) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 μM) was not modified in the presence of cAMP (10 μM) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected. Conclusions: Ivabradine inhibits I f current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I f recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f-channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed. [ABSTRACT FROM AUTHOR]

We present a Fourier grid Hamiltonian-based multidimensional propagator method for multiphoton dissociation dynamics of triatomic molecule in continuous, pulsed, and bichromatic laser field. The method has been successfully applied to the photodissociation dynamics of HCN molecule, i.e., collinear geometry. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [ABSTRACT FROM AUTHOR]

The hyperpolarization-activated current ( Ih) contributes to intrinsic properties and network responses of neurons. Its biophysical properties depend on the expression profiles of the underlying hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and the presence of cyclic AMP (cAMP) that potently and differentially modulates Ih conducted by HCN1, HCN2 and/or HCN4. Here, we studied the properties of Ih in hippocampal CA1 pyramidal cells, the developmental evolution of the HCN-subunit isoforms that contribute to this current, and their interplay with age-dependent free cAMP concentrations, using electrophysiological, molecular and biochemical methods. Ih amplitude increased progressively during the first four postnatal weeks, consistent with the observed overall increased expression of HCN channels. Activation kinetics of the current accelerated during this period, consonant with the quantitative reduction of mRNA and protein expression of the slow-kinetics HCN4 isoform and increased levels of HCN1. The sensitivity of Ih to cAMP, and the contribution of the slow component to the overall Ih, decreased with age. These are likely a result of the developmentally regulated transition of the complement of HCN channel isoforms from cAMP sensitive to relatively cAMP insensitive. Thus, although hippocampal cAMP concentrations increased over twofold during the developmental period studied, the coordinated changes in expression of three HCN channel isoforms resulted in reduced effects of this signalling molecule on neuronal h currents. [ABSTRACT FROM AUTHOR]

Purpose: The hyperpolarization-activated cation current (IH) has been proposed to play a role in some forms of epileptogenesis, as it critically regulates synaptic integration and intrinsic excitability of principal limbic neurons and can be pathologically altered after experimentally induced seizures. In hippocampal CA1 pyramidal neurons, IH is functionally decreased after kainate-induced status epilepticus in adult rats but is increased after hyperthermia-induced seizures in immature rat pups. This study aimed to determine whether and how IH may be altered in CA1 pyramidal neurons after seizure-inducing global hypoxia in the neonatal brain. Methods: Seizures were induced in rat pups on postnatal day 10 by 14- to 16-min exposure to 5–7% O2. Whole-cell patch-clamp recordings were obtained from hippocampal CA1 pyramidal neurons in slices 30 min to 3 days after hypoxia treatment, and from control age-matched littermates. IH was isolated under voltage-clamp by subtracting current responses to hyperpolarizing voltage steps before and during application of the IH blocker ZD 7288 (100 μ M). Results: IH was significantly decreased in pyramidal neurons from the hypoxia-treated group compared with controls (p < 0.001; 19 controls; 15 hypoxia). Analyses of tail currents and activation kinetics indicated no statistically significant differences between groups in the voltage dependence or time constants of activation. Conclusions: These data indicate that a single episode of neonatal hypoxia that induces seizures can persistently decrease IH in CA1 pyramidal neurons, raising this as a potential contributing mechanism to epileptogenesis in this setting. Our findings further indicate that the consequences of seizures for IH may depend more on seizure etiology than on maturational stage. [ABSTRACT FROM AUTHOR]

Although the depressant effects of the general anesthetic propofol on thalamocortical relay neurons clearly involve γ-aminobutyric acid (GABA)A receptors, other mechanisms may be involved. The hyperpolarization-activated cation current ( Ih) regulates excitability and rhythmic firing in thalamocortical relay neurons in the ventrobasal (VB) complex of the thalamus. Here we investigated the effects of propofol on Ih-related function in vitro and in vivo. In whole-cell current-clamp recordings from VB neurons in mouse (P23–35) brain slices, propofol markedly reduced the voltage sag and low-threshold rebound excitation that are characteristic of the activation of Ih. In whole-cell voltage-clamp recordings, propofol suppressed the Ih conductance and slowed the kinetics of activation. The block of Ih by propofol was associated with decreased regularity and frequency of δ-oscillations in VB neurons. The principal source of the Ih current in these neurons is the hyperpolarization-activated cyclic nucleotide-gated (HCN) type 2 channel. In human embryonic kidney (HEK)293 cells expressing recombinant mouse HCN2 channels, propofol decreased Ih and slowed the rate of channel activation. We also investigated whether propofol might have persistent effects on thalamic excitability in the mouse. Three hours following an injection of propofol sufficient to produce loss-of-righting reflex in mice (P35), Ih was decreased, and this was accompanied by a corresponding decrease in HCN2 and HCN4 immunoreactivity in thalamocortical neurons in vivo. These results suggest that suppression of Ih may contribute to the inhibition of thalamocortical activity during propofol anesthesia. Longer-term effects represent a novel form of propofol-mediated regulation of Ih. [ABSTRACT FROM AUTHOR]

FeOx, TiO2, and Fe–Ti–Ox catalysts were synthesized and used in the catalytic hydrolysis of hydrogen cyanide (HCN). Nearly 100% HCN conversion was achieved at 250 °C over the Fe–Ti–Ox catalyst. TiO2 rutile was detected over TiO2, but not over Fe–Ti–Ox, which suggested that the interaction between Fe and Ti species could inhibit the TiO2 phase transition. Furthermore, the interaction between Fe and Ti species over Fe–Ti–Ox could promote the selectivity of NH3 and CO. The mechanism of hydrolysis of HCN over FeOx, TiO2, and Fe–Ti–Ox can be given as follows: HCN + H2O → methanamide → ammonium formate → formic acid → H2O + CO. [ABSTRACT FROM AUTHOR]

Background: Ivabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN-channels. This study investigated the propensity of ivabradine to interact with KCNH2-encoded human Ether-à-go-go-Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia., Methods and Results: Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. Ih ERG was inhibited with an IC50 of 2.07 μmol/L for the hERG 1a isoform and 3.31 μmol/L for coexpressed hERG 1a/1b. The voltage and time-dependent characteristics of Ih ERG block were consistent with preferential gated-state-dependent channel block. Inhibition was partially attenuated by the N588K inactivation-mutant and the S624A pore-helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK-based homology model of hERG, the 2 aromatic rings of the drug could form multiple π-π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea-pig Langendorff-perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve., Conclusions: Ivabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits Ih ERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)