Simulating patterns of excitation, repolarization and action potential duration with cardiac Bidomain and Monodomain models

Parallel numerical simulations of excitation and recovery in three-dimensional myocardial domains are presented. The simulations are based on the anisotropic Bidomain and Monodomain models, including intramural fiber rotation and orthotropic or axisymmetric anisotropy of the intra- and extra-cellular conductivity tensors. The Bidomain model consist of a system of two reaction-diffusion equations, while the Monodomain model consists of one reaction-diffusion equation. Both models are coupled with the phase I Luo-Rudy membrane model describing the ionic currents. Simulations of excitation and repolarization sequences on myocardial slabs of different sizes show how the distribution of the action potential durations (APD) is influenced by both the anisotropic electrical conduction and the fiber rotation. This influence occurs in spite of the homogeneous intrinsic properties of the cell membrane. The APD dispersion patterns are closely correlated to the anisotropic curvature of the excitation wavefront.     

The effects of static magnetic field on action potential propagation and excitation recovery in nerve

Calculations using the Hodgkin–Huxley and one-dimensional cable equations have been performed to determine the expected sensitivity of conduction and refractoriness to changes in the time constant of sodium channel deactivation at negative potentials, as reported experimentally by Rosen (Bioelectromagnetics 24 (2003) 517) when voltage-gated sodium channels are exposed to a 125 mT static magnetic field. The predicted changes in speed of conduction and refractory period are very small.     

Temperature regulates the arrhythmogenic activity of pulmonary vein cardiomyocytes

Temperature plays an important role in the electrophysiology of cardiomyocytes. Pulmonary veins (PVs) are known to initiate paroxysmal atrial fibrillation. The effects of temperature on the arrhythmogenic activity of rabbit single PV and atrial cardiomyocytes were assessed using the whole-cell clamp technique. PV cardiomyocytes had different beating rates at low (22-25 degrees C), normal (38-39 degrees C) and high (40-41 degrees C) temperatures (0.9 +/- 0.1, 3.2 +/- 0.4, 6.4 +/- 0.6 Hz, respectively; p < 0.001). There were different action potential durations and incidences of delayed afterdepolarization in PV cardiomyocytes with pacemaker activity (31, 59, 63%; p < 0.05), PV cardiomyocytes without pacemaker activity (16, 47, 60%; p < 0.001), and atrial myocytes (0, 0, 21%; p < 0.05). However, oscillatory afterpotentials were only found in PV cardiomyocytes with pacemaker activity at normal (50%) or high (68%) temperatures, but not at low temperatures (p < 0.001). Both PV and atrial cardiomyocytes had larger transient inward currents and inward rectified currents at high temperatures. Additionally, PV cardiomyocytes with and without pacemaker activity had larger pacemaker currents at higher temperatures. This study demonstrated that PV cardiomyocytes have an increase in arrhythmogenic activity at high temperatures because of enhanced automaticity, induced triggered activity, or shortening of action potential duration.     

Centrin is essential for the activity of the ciliary reversal-coupled voltage-gated Ca2+ channels

Voltage-gated Ca(2+) channels play a critical role in controlling Ca(2+) entry in various cells. Ciliary reversal in Paramecium depends on the Ca(2+) influx through voltage-gated Ca(2+) channels on the ciliary membrane. One of the voltage-gated Ca(2+) channel mutants in Paramecium caudatum, cnrC, neither produces Ca(2+) action potentials nor responds to any depolarizing stimuli. Here, we report that the cnrC(+) gene product is P. caudatum centrin (Pccentrin1p), a member of the Ca(2+)-binding EF-hand protein superfamily. The Pccentrin1p gene of cnrC was found to contain a single-base deletion, a mutation that caused the loss of the fourth EF-hand of Pccentrin1p. Moreover, the wild-type Ca(2+) channel function was impaired by Pccentrin1p gene silencing, leading to the loss of current-evoked Ca(2+) action potentials and stimulated ciliary reversal. These results demonstrate that Pccentrin1p is indispensable for the activity of the voltage-gated Ca(2+) channels that control ciliary reversal in Paramecium.     

Electrophysiological responses to salts from antennal chaetoid taste sensilla of the ground beetle Pterostichus aethiops

Antennal gustatory sensilla of the ground beetle Pterostichus aethiops (Pz., 1797) (Coleoptera, Carabidae) respond to salts, the three sensory cells, A-, B- and C-cells, producing action potentials that are distinguished by differences in their shape, amplitude, duration and polarity of spikes. The B-cell (salt cell) was highly sensitive to both ionic composition and concentration of the tested nine salt solutions showing phasic-tonic type of reaction with a pronounced phasic component. The stimulating effect was dominated by the cations involved, and in most cases, monovalent cations were more effective stimuli than divalent cations. Salt concentration/response relations were tested with NaCl at 1, 10, 100 and 1000 mmol l⁻¹: mean firing rates increased from 0.8 to 44 spikes per first second of the response, respectively. The pH value of the stimulating solutions also influenced the B-cell rate of firing. By contrast, the pH level of stimulus solutions influenced the A-cells’ phasic-tonic response more than the ionic composition or concentration of these solutions. Compared to a standard 100 mmol l⁻¹ salt (NaCl) solution (pH 6.3), alkaline solutions of the salts NaCH₃COO, Na₂HPO₄ and Na₂B₄O₇ (pH 7.9, 8.5 and 9.3, respectively, all 100 mmol l⁻¹) induced remarkably stronger responses in the A-cell. On the other hand, the reaction to an acid solution of NaH₂PO₄ (pH 4.5, 100 mmol l⁻¹) was minimal. A-cell responses to neutral salts like NaCl, KCl, CaCl₂, MgCl₂ and C₅H₁₄NOCl (pH 6.1-6.5) varied largely in strength. Very low or no responses were observed with chlorides of divalent cations, CaCl₂ and MgCl₂, and choline chloride (C₅H₁₄NOCl), indicating that the ionic composition of the solutions also affected A-cell responses. Neural activity of the C-cell was not influenced by the salt solutions tested.     

Cytotoxic phenylethanol glycosides from Psidium guaijava seeds

Phytochemical investigations of the acetone extract of Psidium guaijava seeds has led to the isolation of five known flavonoid glycosides, two phenolic glycosides and two new phenylethanoid glycosides which have been identified as 1-O-3,4-dimethoxy-phenylethyl-4-O-3,4-dimethoxy cinnamoyl-6-O-cinnamoyl-beta-D-glucopyranose and 1-O-3,4-dimethoxyphenylethyl-4-O-3,4-dimethoxy cinnamoyl-beta-D-glucopyranose, on the basis of chemical, physical and spectroscopic methods of analysis.     

Anion modulation of the slowly activating vacuolar channel

A series of n-alkanols and phenyl-substituted n-alkanols (Φ-alkanols) of increasing chain length and phenol were characterized for their ability to block action potentials (APs) in frog sciatic nerves. APs were recorded using the single sucrose-gap method. The degree of AP attenuation when the nerve was exposed to different concentrations of an alcohol was used to construct dose-response curves. The reciprocals of the half-blocking doses (ED₅₀s) were used to obtain a measure of the potency of the alcohols. For n-alkanols and Φ-alkanols, increasing the chain length by the addition of a methylene group increased the potency on average by 3.1 for both groups of alkanols. The addition of a phenyl group caused a potency increase that ranged between the values of 77 and 122. The ED₅₀ for both groups of alkanols could not be solely predicted by the log octanol-water partition coefficient (K _OW ). Using linear solvation energy relations (LSER), the log ED₅₀ could be described as a linear combination of the intrinsic (van der Waals) molar volume (V _I ), polarity (P), and hydrogen bond acceptor basicity (β) and donor acidity (α). Size alone could not predict the ED₅₀ for both n-alkanols and Φ-alkanols. The results are consistent with the hypothesis that alkanols bind to and interact with Na channels to cause AP block. Phenyl group addition to an alkanol markedly increases the molecule's potency. Received: 11 August 2000/Revised: 21 December 2000     

Asymptotics of the total net direct pharmacological effect for large drug doses

The direct pharmacological effect E is described by the E _max model relating E to the drug plasma concentration C _p . The area under the effect vs. time curve (AUC _E ) is used as the measurement of the total net pharmacological effect. The drug plasma concentrations are solutions of compartmental systems of ordinary differential equations with the input terminated after a finite time and controlled in a proportional manner by a single dose-like parameter. The asymptotics of the time derivative of C _p for large doses are derived and used as conditions which have to be satisfied by functions for which the asymptotics of the integral defining AUC _E are derived. The AUC _E is proportional to the time T _C>EC50 for which the drug concentration stays above the threshold level EC ₅₀. The threshold EC ₅₀ denotes the drug plasma concentration which elicits 50% of the maximum effect. The parameter T _C>EC50 is proportional to the logarithm of drug dose for large doses and its asymptotics is calculated up to the order o(1) as dose increases to infinity. The results are applied to basic pharmacokinetic systems. Received: 7 December 1999 / Revised version: 23 May 2000 / Published online: 23 October 2000     

Effects of Protonophores on Membrane Electrical Characteristics in NG108-15 Cells

Studies were conducted to determine the effects of bath application of the protonophores carbonyl cyanide m-chlorophenylhydrazone (CCCP) and carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP) on membrane electrical characteristics of differentiated NG108-15 (neuroblastoma X glioma hybrid) cells. Membrane resting potential (V_m), input resistance (R_in) and electrically induced action potential generation were measured using intracellular micro-electrode techniques. Both compounds produced concentration-dependent depolarization rather than the hyperpolarization commonly found with other central mammalian neurons. CCCP and FCCP also reduced R_in and disrupted the generation of action potentials in a concentration-dependent manner. The contribution of the observed alterations to the in vivo toxicity of these compounds remains to be established.     

Current strategies for the treatment of inborn errors of metabolism

Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.