The Antiarrhythmic Action of the Na+/Ca2+ Exchanger Inhibitor SEA0400 on Drug-Induced Long QT Syndrome Depends on the Severity of Proarrhythmic Conditions in Anesthetized Atrioventricular Block Rabbits.

To clarify the pharmacological properties of the Na+/Ca2+ exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K+ current (IKr) blocker-induced torsade de pointes (TdP) in isoflurane-anesthetized rabbits. Atrioventricular block was induced in rabbits using a catheter ablation technique, and the monophasic action potential (MAP) of the right ventricle was measured under electrical pacing at 60 beats/min. In non-treated control animals, intravenous administration of low-dose (0.3 mg/kg) or high-dose nifekalant (3 mg/kg) prolonged the MAP duration (MAP90) by 113 ± 11 ms (n = 5) and 237 ± 39 ms (n = 5), respectively, where TdP was induced in 1/5 animals treated with a low dose and in 3/5 animals treated with a high dose of nifekalant. In SEA0400-treated animals, low- and high-dose nifekalant prolonged the MAP90 by 65 ± 13 ms (n = 5) and 230 ± 20 ms (n = 5), respectively. No TdP was induced by the low dose but 1/5 animals treated with a high dose of nifekalant developed TdP. In verapamil-treated animals, low-dose and high-dose nifekalant prolonged MAP90 by 50 ± 12 ms (n = 5) and 147 ± 30 ms (n = 5), respectively, without inducing TdP. These results suggest that SEA0400 has the potential to inhibit low-dose nifekalant-induced TdP by suppressing the MAP-prolonging action of nifekalant, whereas the drug inhibited high-dose nifekalant-induced TdP without affecting the MAP-prolonging action of nifekalant. This may reveal that, in contrast to verapamil, the antiarrhythmic effects of SEA0400 on IKr blocker-induced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

Role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in the anesthetized atrioventricular block rabbit.

We analyzed role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia was induced by atrioventricular node ablation, and the ventricle was electrically driven at a constant rate of 60 beats/min throughout the experiments to prevent rate-dependent modification by the IKr blocker in ventricular repolarization phase. Nifekalant (3 mg/kg per 10 min, n = 5) prolonged the duration of monophasic action potential (MAP90) by +178 ± 43 ms, increased the short-term variability of repolarization (STV) to 4.2 ± 1.2 ms, and induced torsade de pointes (TdP) in 1 animal. In the presence of methoxamine (n = 5), nifekalant prolonged the MAP90 by +328 ± 32 ms, increased the STV to 8.0 ± 1.0 ms, and induced TdP in 2 animals. In the presence of prazosin and methoxamine (n = 5), nifekalant prolonged the MAP90 by +267 ± 22 ms, increased the STV to 9.2 ± 3.6 ms, and induced no TdP. These results suggest that cardiac α1-adrenoreceptor activation by methoxamine essentially sensitizes the rabbit heart to nifekalant-induced QT interval prolongation, leading to the onset of TdP.

The anaesthetized rabbit with acute atrioventricular block provides a new model for detecting drug-induced Torsade de Pointes.

BACKGROUND AND PURPOSE: Several rabbit proarrhythmia models have been developed using genetic or pharmacological methods to suppress the slow component of delayed rectifier K+ currents in the ventricle, leading to reduction of the repolarization reserve. Here we have characterized a novel rabbit in vivo proarrhythmia model with severe bradycardia caused by acute atrioventricular block (AVB). EXPERIMENTAL APPROACH: Bradycardia was induced in isoflurane-anaesthetized rabbits by inducing AVB with catheter ablation, and the ventricle was electrically driven at 60 beats min-1 throughout the experiment except when extrasystoles appeared. We assessed the effects of two antiarrhythmics, two quinolone antibiotics and one antipsychotic drug, which were chosen as positive drugs (dofetilide, sparfloxacin and haloperidol) and negative drugs (amiodarone and moxifloxacin) for induction of Torsades de Pointes (TdP). KEY RESULTS: In our model, TdP arrhythmias appeared with high reproducibility after i.v. dofetilide (10-100 µg·kg-1 ) in five out of six rabbits, sparfloxacin (30 mg·kg-1 ) in three out of six rabbits and haloperidol (0.3-3 mg·kg-1 ) in two out of six rabbits. The lethal arrhythmias repeatedly appeared and were accompanied with prolongation of the QT interval and early afterdepolarization-like phenomena. Neither amiodarone (0.3-10 mg·kg-1 , n = 6) nor moxifloxacin (3-30 mg·kg-1 , n = 6) induced such arrhythmias, even when QT intervals were prolonged. CONCLUSIONS AND IMPLICATIONS: These results suggest that our model of the unremodelled and bradycardic heart of the anaesthetized rabbit is a useful test system for the detection of drug-induced TdP arrhythmias.

Quantitative Mass Density Image Reconstructed from the Complex X-Ray Refractive Index.

We demonstrate a new analytical X-ray computed tomography technique for visualizing and quantifying the mass density of materials comprised of low atomic number elements with unknown atomic ratios. The mass density was obtained from the experimentally observed ratio of the imaginary and real parts of the complex X-ray refractive index. An empirical linear relationship between the X-ray mass attenuation coefficient of the materials and X-ray energy was found for X-ray energies between 8 keV and 30 keV. The mass density image of two polymer fibers was quantified using the proposed technique using a scanning-type X-ray microbeam computed tomography system equipped with a wedge absorber. The reconstructed mass density agrees well with the calculated one.

Scanning hard x-ray differential phase contrast imaging with a double wedge absorber.

Two-directional differential phase contrast images were measured using an x-ray microbeam and a double wedge absorber. The wedge absorber converts the displacement of an x-ray beam that is refracted by an object into change of x-ray intensity. The double wedge absorber made it possible to detect values of two-directional refraction angle with microrad sensitivity simultaneously. By Fourier integration of two-directional phase gradients calculated from the refraction angle instead of line integration of one-directional phase gradients, we obtained a quantitative phase map without artifacts even when only a part of the boundaries of the object were in the field of view. One of the characteristics of this technique is flexibility in a sensitivity of the phase gradient. By changing of shape or material of the wedge absorber, it is comparatively easy to control the detection limit of the refraction angle.

In situ observation of water distribution and behaviour in a polymer electrolyte fuel cell by synchrotron X-ray imaging.

In situ visualization of the distribution and behaviour of water in a polymer electrolyte fuel cell during power generation has been demonstrated using a synchrotron X-ray imaging technique. Images were recorded using a CCD detector combined with a scintillator (Gd(2)O(2)S:Tb) and relay lens system, which were placed at 2.0 m or 2.5 m from the fuel cell. The images were measured continuously before and during power generation, and data on cell performance was recorded. The change of water distribution during power generation was obtained from X-ray images normalized with the initial state of the fuel cell. Compared with other techniques for visualizing the water in fuel cells, this technique enables the water distribution and behaviour in the fuel cell to be visualized during power generation with high spatial resolution. In particular, the effects of the specifications of the gas diffusion layer on the cathode side of the fuel cell on the distribution of water were efficiently identified. This is a very powerful technique for investigating the mechanism of water flow within the fuel cell and the relationship between water behaviour and cell performance.

Three-dimensional visualization of the inner structure of single crystals by step-scanning white X-ray section topography.

Visualization of the three-dimensional distribution of the crystal defects of large single crystals of calcium fluoride has been demonstrated by white X-ray section topography using sheet-like X-rays (BL28B2 at SPring-8). An image of the three-dimensional distribution of the crystal defects was reconstructed by stacking section topographs, which expressed the images of cross sections of the sample. The section topographs were recorded using a CMOS flat-panel imager or a CCD detector combined with scintillator (Gd(2)O(2)S:Tb) and relay lens system. The section topographs were measured by repeating cycles of exposure and sample translation along the direction perpendicular to the top face of the sample. Using high-brilliance and high-energy white X-rays ( approximately 60 keV) efficiently, visualization of the three-dimensional structure of subgrains of a sample of up to 60 mm in diameter was achieved. Furthermore, the three-dimensional distribution of the glide plane in the crystal was visualized by reconstructing the linear contrast of the glide plane.

Silica films with a single-crystalline mesoporous structure.

Films of mesoporous materials attract broad interest because of their wide applicability in the fields of optics and electronics. Although many of these films have a regular local porous structure, the structural regularity has not been used practically yet because of difficulties in its control on macroscopic scales. Here, we demonstrate the preparation of mesoporous silica films whose porous structure can be described as a single crystal, that is, a long-range order of cage-like pores is maintained over centimetre scales. These films have a three-dimensional hexagonal (space group P6(3)/mmc) porous structure, and the in-plane arrangement of the pores is strictly controlled by a polymeric substrate surface that has been treated by rubbing. This new class of single-crystalline films with mesoscopic periodic structure is a significant breakthrough in bottom-up nanotechnology, and could lead to novel devices, for example, optics in a soft X-ray region, and quantum electronics.