Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes.

BACKGROUND: Atrial-ventricular differences in voltage-gated Na+ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na+ channel blocker ranolazine that has been shown to be safe and well tolerated in patients. OBJECTIVE: The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na+ currents. METHODS: The fast and late components of whole-cell voltage-gated Na+ currents (respectively, I Na and I NaL) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes. RESULTS: Atrial I Na activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular I Na. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I NaL activated by 3 nM ATX-II (IC50s ∼200 nM). Eleclazine (10 µM) inhibited I Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I Na from inactivation in both cell types. CONCLUSIONS: Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I Na. The more negative voltage dependence of I Na activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.

Pore Structure Changes Occur During CO2 Injection into Carbonate Reservoirs.

Observations and modeling studies have shown that during CO2 injection into underground carbonate reservoirs, the dissolution of CO2 into formation water forms acidic brine, leading to fluid-rock interactions that can significantly impact the hydraulic properties of the host formation. However, the impacts of these interactions on the pore structure and macroscopic flow properties of host rock are poorly characterized both for the near-wellbore region and deeper into the reservoir. Little attention has been given to the influence of pressure drop from the near-wellbore region to reservoir body on disturbing the ionic equilibrium in the CO2-saturated brine and consequent mineral precipitation. In this paper, we present the results of a novel experimental procedure designed to address these issues in carbonate reservoirs. We injected CO2-saturated brine into a composite core made of two matching grainstone carbonate core plugs with a tight disk placed between them to create a pressure profile of around 250 psi resembling that prevailing in reservoirs during CO2 injection. We investigated the impacts of fluid-rock interactions at pore and continuum scale using medical X-ray CT, nuclear magnetic resonance, and scanning electron microscopy. We found that strong calcite dissolution occurs near to the injection point, which leads to an increase in primary intergranular porosity and permeability of the near injection region, and ultimately to wormhole  formation. The strong heterogeneous dissolution of calcite grains leads to the formation of intra-granular micro-pores. At later stages of the dissolution, the internal regions of ooids become accessible to the carbonated brine, leading to the formation of moldic porosity. At distances far from the injection point, we observed minimal or no change in pore structure, pore roughness, pore populations, and rock hydraulic properties. The pressure drop of 250 psi slightly disturbed the chemical equilibrium of the system, which led to minor precipitation of sub-micron sized calcite crystals but due to the large pore throats of the rock, these deposits had no measurable impact on rock permeability. The trial illustrates that the new procedure is valuable for investigating fluid-rock interactions by reproducing the geochemical consequences of relatively steep pore pressure gradients during CO2 injection.

Hot-Spotting with Thermal Scanning: A Ligand- and Structure-Independent Assessment of Target Ligandability.

Evaluating the ligandability of a protein target is a key component when defining hit-finding strategies or when prioritize among drug targets. Computational as well as biophysical approaches based on nuclear magnetic resonance (NMR) fragment screening are powerful approaches but suffer from specific constraints that limit their usage. Here, we demonstrate the applicability of high-throughput thermal scanning (HTTS) as a simple and generic biophysical fragment screening method to reproduce assessments from NMR-based screening. By applying this method to a large set of proteins we can furthermore show that the assessment is predictive of the success of high-throughput screening (HTS). The few divergences for targets of low ligandability originate from the sensitivity differences of the orthogonal biophysical methods. We thus applied a new strategy making use of modulations in the solvent structure to improve assay sensitivity. This novel approach enables improved ligandability assessments in accordance with NMR-based assessments and more importantly positions the methodology as a valuable option for biophysical fragment screening.

Research of CO2 and N2 Adsorption Behavior in K-Illite Slit Pores by GCMC Method.

Understanding the adsorption mechanisms of CO2 and N2 in illite, one of the main components of clay in shale, is important to improve the precision of the shale gas exploration and development. We investigated the adsorption mechanisms of CO2 and N2 in K-illite with varying pore sizes at the temperature of 333, 363 and 393 K over a broad range of pressures up to 30 MPa using the grand canonical Monte Carlo (GCMC) simulation method. The simulation system is proved to be reasonable and suitable through the discussion of the impact of cation dynamics and pore wall thickness. The simulation results of the excess adsorption amount, expressed per unit surface area of illite, is in general consistency with published experimental results. It is found that the sorption potential overlaps in micropores, leading to a decreasing excess adsorption amount with the increase of pore size at low pressure, and a reverse trend at high pressure. The excess adsorption amount increases with increasing pressure to a maximum and then decreases with further increase in the pressure, and the decreasing amount is found to increase with the increasing pore size. For pores with size greater larger than 2 nm, the overlap effect disappears.

Lattice Boltzmann modeling of permeability in porous materials with partially percolating voxels.

A partial-bounce-back lattice Boltzmann model has been used to simulate flow on a lattice consisting of cubic voxels with a locally varying effective percolating fraction. The effective percolating fraction of a voxel is the total response to the partial-bounce-back techniques for porous media flow due to subvoxel fine structures. The model has been verified against known analytic solutions on two- and three-dimensional regular geometries, and has been applied to simulate flow and permeabilities of two real-world rock samples. This enables quantitative determination of permeability for problems where voxels cannot be adequately segmented as discrete compositions. The voxel compositions are represented as volume fractions of various material phases and void. The numerical results have shown that, for the tight-sandstone sample, the bulk permeability is sensitive to the effective percolating fraction of calcite. That is, the subvoxel flow paths in the calcite phase are important for bulk permeability. On the other hand, flow in the calcite phase in the sandstone sample makes an insignificant contribution to the bulk permeability. The calculated permeability value for the sandstone sample is up to two orders of magnitude greater than the tight sandstone. This model is generic and could be applied to other oil and gas reservoir media or to material samples.