Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806

Transient outward potassium current (Ito) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of Ito may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine Ito This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular Ito Whole cell patch-clamp recordings of Ito and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 μmol/L NS5806 increased ventricular Ito with a leftward shift in Ito activation and accelerated restitution. At higher concentrations, stimulation of Ito was followed by inhibition. The EC50 for stimulation was 1.6 μmol/L and inhibition had an IC50 of 40.7 μmol/L. NS5806 only inhibited atrial Ito (IC50 of 18 μmol/L) and produced a modest leftward shifts in Ito activation and inactivation, without an effect on restitution. 10 μmol/L NS5806 shortened ventricular action potential duration (APD) at APD20-APD90 but prolonged atrial APD NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na(+) channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial Ito NS5806 discriminates between rabbit ventricular and atrial Ito, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac Ito.</p

Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806

Transient outward potassium current (I(to)) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation–contraction coupling. Small molecule activators of I(to) may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I(to). This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I(to). Whole cell patch‐clamp recordings of I(to) and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 μmol/L NS5806 increased ventricular I(to) with a leftward shift in I(to) activation and accelerated restitution. At higher concentrations, stimulation of I(to) was followed by inhibition. The EC (50) for stimulation was 1.6 μmol/L and inhibition had an IC (50) of 40.7 μmol/L. NS5806 only inhibited atrial I(to) (IC (50) of 18 μmol/L) and produced a modest leftward shifts in I(to) activation and inactivation, without an effect on restitution. 10 μmol/L NS5806 shortened ventricular action potential duration (APD) at APD (20)‐APD (90) but prolonged atrial APD. NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio‐selective effect on Na(+) channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I(to). NS5806 discriminates between rabbit ventricular and atrial I(to,) with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I(to)

Multiple ion channel block by the cation channel inhibitor SKF-96365 in myocytes from the rabbit atrioventricular node

The atrioventricular node (AVN) of the cardiac conduction system coordinates atrial–ventricular excitation and can act as a subsidiary pacemaker. Recent evidence suggests that an inward background sodium current, I (B,Na), carried by nonselective cation channels (NSCCs), contributes to AVN cell pacemaking. The study of the physiological contribution of I (B,Na) has been hampered, however, by a lack of selective pharmacological antagonists. This study investigated effects of the NSCC inhibitor SKF‐96365 on spontaneous activity, I (B,Na), and other ionic currents in AVN cells isolated from the rabbit. Whole‐cell patch‐clamp recordings of action potentials (APs) and ionic currents were made at 35–37°C. A concentration of 10 μmol/L SKF‐96365 slowed spontaneous action potential rate by 13.9 ± 5.3% (n = 8) and slope of the diastolic depolarization from 158.1 ± 30.5 to 86.8 ± 30.5 mV sec(−1) (P < 0.01; n = 8). Action potential upstroke velocity and maximum diastolic potential were also reduced. Under I (B,Na)‐selective conditions, 10 μmol/L SKF‐96365 inhibited I (B,Na) at −50 mV by 36.1 ± 6.8% (n = 8); however, effects on additional channel currents were also observed. Thus, the peak l‐type calcium current (I (Ca,L)) at +10 mV was inhibited by 38.6 ± 8.1% (n = 8), while the rapid delayed rectifier current, I (Kr), tails at −40 mV following depolarization to +20 mV were inhibited by 55.6 ± 4.6% (n = 8). The hyperpolarization‐activated current, I (f), was unaffected by SKF‐96365. Collectively, these results indicate that SKF‐96365 exerts a moderate inhibitory effect on I (B,Na) and slows AVN cell pacemaking. However, additional effects of the compound on I (Ca,L) and I (Kr) confound the use of SKF‐96365 to dissect out selectively the physiological role of I (B,Na) in the AVN

Electrophysiological properties of myocytes isolated from the mouse atrioventricular node:L-type ICa, IKr, If, and Na-Ca exchange

The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. This study investigated the electrophysiology of cells isolated from the AVN region of adult mouse hearts, and compared murine ionic current magnitude with that of cells from the more extensively studied rabbit AVN. Whole-cell patch-clamp recordings of ionic currents, and perforated-patch recordings of action potentials (APs), were made at 35–37°C. Hyperpolarizing voltage commands from −40 mV elicited a Ba(2+)-sensitive inward rectifier current that was small at diastolic potentials. Some cells (Type 1; 33.4 ± 2.2 pF; n = 19) lacked the pacemaker current, I(f), whilst others (Type 2; 34.2 ± 1.5 pF; n = 21) exhibited a clear I(f), which was larger than in rabbit AVN cells. On depolarization from −40 mV L-type Ca(2+) current, I(C)(a,L), was elicited with a half maximal activation voltage (V(0.5)) of −7.6 ± 1.2 mV (n = 24). I(C)(a,L) density was smaller than in rabbit AVN cells. Rapid delayed rectifier (I(K)(r)) tail currents sensitive to E-4031 (5 μmol/L) were observed on repolarization to −40 mV, with an activation V(0.5) of −10.7 ± 4.7 mV (n = 8). The I(K)(r) magnitude was similar in mouse and rabbit AVN. Under Na-Ca exchange selective conditions, mouse AVN cells exhibited 5 mmol/L Ni-sensitive exchange current that was inwardly directed negative to the holding potential (−40 mV). Spontaneous APs (5.2 ± 0.5 sec(−1); n = 6) exhibited an upstroke velocity of 37.7 ± 16.2 V/s and ceased following inhibition of sarcoplasmic reticulum Ca(2+) release by 1 μmol/L ryanodine, implicating intracellular Ca(2+) cycling in murine AVN cell electrogenesis

Data from a comparative proteomic analysis of tumor-derived lung-cancer CD105+ endothelial cells

AbstractIncreasing evidence indicates that tumor-derived endothelial cells (TECs) are more relevant for the study of tumor angiogenesis and for screening antiangiogenic drugs than normal ECs (NECs). In this data article, high-purity (>98%) primary CD105+ NECs and TECs purified from a mouse Lewis lung carcinoma model bearing 0.5cm tumors were identified using 2D-PAGE and Matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). All the identified proteins were categorized functionally by Gene Ontology (GO) analysis, and gene-pathway annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, protein–protein interaction networks were also built. The proteomics and bioinformatics data presented here provide novel insights into the molecular characteristics and the early modulation of the TEC proteome in the tumor microenvironment

Structural and electronic origin of the magnetic structures in hexagonal LuFeO3_3

Using combined theoretical and experimental approaches, we studied the structural and electronic origin of the magnetic structure in hexagonal LuFeO$_3$. Besides showing the strong exchange coupling that is consistent with the high magnetic ordering temperature, the previously observed spin reorientation transition is explained by the theoretically calculated magnetic phase diagram. The structural origin of this spin reorientation that is responsible for the appearance of spontaneous magnetization, is identified by theory and verified by x-ray diffraction and absorption experiments.Comment: 5 pages, 2 tables and 4 figures, Please contact us for the supplementary material. Accepted in Phys. Rev. B, in productio

Dynamic stress response and fatigue life of cantilever beam under non-Gaussian base excitation

The stress response of cantilever beam to non-Gaussian random base excitation is investigated based on Monte-Carlo simulation. First, the statistical properties and spectral characteristics of non-Gaussian random vibrations are analyzed qualitatively; and the conclusion is that spectral method based on power spectrum density (PSD) is not applicable for non-Gaussian random vibrations. Second, the stress response formula of cantilever beam under non-Gaussian random base excitations is established in the time-domain, and the factors influencing the output kurtosis are subsequently determined. Two numerical examples representing different practical situations are analyzed in detail. The discrepancies of the stress responses to Gaussian, steady non-Gaussian and burst non-Gaussian base excitations are analyzed in terms of root mean square (RMS), kurtosis and fatigue damage. The transmissibility of RMS and high-kurtosis of steady non-Gaussian random base excitation is different from that of burst non-Gaussian case. Finally, the fatigue life corresponding to every base excitation is calculated using the rainflow method in conjunction with the Palmgren-Miner rule. Finite element analysis is also carried out for validation. The predicted fatigue lives corresponding to Gaussian, steady non-Gaussian and burst non-Gaussian base excitations are compared quantitatively. Finally, in the fatigue damage point of view, the discrepancies among the three kinds of random base excitations are summarized

Shaping nanoparticles with hydrophilic compositions and hydrophobic properties as nanocarriers for antibiotic delivery

Inspired by the lotus effect in nature, surface roughness engineering has led to novel materials and applications in many fields. Despite the rapid progress in superhydrophobic and superoleophobic materials, this concept of Mother Nature’s choice is yet to be applied in the design of advanced nanocarriers for drug delivery. Pioneering work has emerged in the development of nanoparticles with rough surfaces for gene delivery; however, the preparation of nanoparticles with hydrophilic compositions but with enhanced hydrophobic property at the nanoscale level employing surface topology engineering remains a challenge. Herein we report for the first time the unique properties of mesoporous hollow silica (MHS) nanospheres with controlled surface roughness. Compared to MHS with a smooth surface, rough mesoporous hollow silica (RMHS) nanoparticles with the same hydrophilic composition show unusual hydrophobicity, leading to higher adsorption of a range of hydrophobic molecules and controlled release of hydrophilic molecules. RMHS loaded with vancomycin exhibits an enhanced antibacterial effect. Our strategy provides a new pathway in the design of novel nanocarriers for diverse bioapplications