Investigation of the Cellular Pharmacological Mechanism and Clinical Evidence of the Multi-Herbal Antiarrhythmic Chinese Medicine Xin Su Ning.

Xin Su Ning (XSN), a China patented and certified multi-herbal medicine, has been available in China since 2005 for treating cardiac ventricular arrhythmia including arrhythmia induced by ischemic heart diseases and viral myocarditis, without adverse reactions being reported. It is vitally important to discover pharmacologically how XSN as a multicomponent medicine exerts its clinical efficacy, and whether the therapeutic effect of XSN can be verified by standard clinical trial studies. In this paper we report our discoveries in a cellular electrophysiological study and in a three-armed, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial.

Biological Relativity Requires Circular Causality but Not Symmetry of Causation: So, Where, What and When Are the Boundaries?

Since the Principle of Biological Relativity was formulated and developed there have been many implementations in a wide range of biological fields. The purpose of this article is to assess the status of the applications of the principle and to clarify some misunderstandings. The principle requires circular causality between levels of organization.

Electrotonic suppression of early afterdepolarizations in the neonatal rat ventricular myocyte monolayer.

Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin-A (AP-A). AP-A-treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs.

How the Hodgkin-Huxley equations inspired the Cardiac Physiome Project.

Early modelling of cardiac cells (1960-1980) was based on extensions of the Hodgkin-Huxley nerve axon equations with additional channels incorporated, but after 1980 it became clear that processes other than ion channel gating were also critical in generating electrical activity. This article reviews the development of models representing almost all cell types in the heart, many different species, and the software tools that have been created to facilitate the cardiac Physiome Project.

Ca²⁺-induced delayed afterdepolarizations are triggered by dyadic subspace Ca2²⁺ affirming that increasing SERCA reduces aftercontractions.

Ca(2+)-induced delayed afterdepolarizations (DADs) are depolarizations that occur after full repolarization. They have been observed across multiple species and cell types. Experimental results have indicated that the main cause of DADs is Ca(2+) overload.

Competing oscillators in cardiac pacemaking: historical background.

Interaction between a membrane oscillator generated by voltage-dependent ion channels and an intracellular calcium signal oscillator was present in the earliest models (1984 to 1985) using representations of the sarcoplasmic reticulum. Oscillatory release of calcium is inherent in the calcium-induced calcium release process. Those historical results fully support the synthesis proposed in the articles in this review series.

Mathematical models of the electrical action potential of Purkinje fibre cells.

Early development of ionic models for cardiac myocytes, from the pioneering modification of the Hodgkin-Huxley giant squid axon model by Noble to the iconic DiFrancesco-Noble model integrating voltage-gated ionic currents, ion pumps and exchangers, Ca(2+) sequestration and Ca(2+)-induced Ca(2+) release, provided a general description for a mammalian Purkinje fibre (PF) and the framework for modern cardiac models. In the past two decades, development has focused on tissue-specific models with an emphasis on the sino-atrial (SA) node, atria and ventricles, while the PFs have largely been neglected. However, achieving the ultimate goal of creating a virtual human heart will require detailed models of all distinctive regions of the cardiac conduction system, including the PFs, which play an important role in conducting cardiac excitation and ensuring the synchronized timing and sequencing of ventricular contraction.

The role of the Na+/Ca2+ exchangers in Ca2+ dynamics in ventricular myocytes.

The role of the Na+/Ca2+ exchanger (NCX) as the main pathway for Ca2+ extrusion from ventricular myocytes is well established. However, both the role of the Ca2+ entry mode of NCX in regulating local Ca2+ dynamics and the role of the Ca2+ exit mode during the majority of the physiological action potential (AP) are subjects of controversy. The functional significance of NCXs location in T-tubules and potential co-localization with ryanodine receptors was examined using a local Ca2+ control model of low computational cost.

Role of pacemaking current in cardiac nodes: insights from a comparative study of sinoatrial node and atrioventricular node.

Cardiac pacemaking in the sinoatrial (SA) node and atrioventricular (AV) node is generated by an interplay of many ionic currents, one of which is the funny pacemaker current (If). To understand the functional role of If in two different pacemakers, comparative studies of spontaneous activity and expression of the HCN channel in mouse SA node and AV node were performed. The intrinsic cycle length (CL) is 179+/-2.

Resistance of cardiac cells to NCX knockout: a model study.

The effects of NCX knockout were determined in a variety of cardiac cell models. Those of the mouse and rat ventricles, and of atrial cells in other species behave similarly to the experiments on mouse ventricle showing only small effects, and considerable tolerance of NCX knockout. Models of ventricular cells with high action potential plateaus, however, are more sensitive and require compensatory mechanisms to adjust other conductance parameters to enable the cells to resist NCX knockout.

Functional significance of Na+/Ca2+ exchangers co-localization with ryanodine receptors.

Co-localization of Na+/Ca2+ exchangers (NCX) with ryanodine receptors (RyRs) is debated. We incorporate local NCX current in a biophysically detailed model of L-type Ca2+ channels (LCCs) and RyRs and study the effect of NCX on the regulation of Ca2+-induced Ca2+ release and the shape of the action potential. In canine ventricular cells, under pathological conditions, e.

Modelling of calcium handling in airway myocytes.

Airway myocytes are the primary effectors of airway reactivity which modulates airway resistance and hence ventilation. Stimulation of airway myocytes results in an increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and the subsequent activation of the contractile apparatus. Many contractile agonists, including acetylcholine, induce [Ca(2+)](i) increase via Ca(2+) release from the sarcoplasmic reticulum through InsP(3) receptors.

Ascending aortic stenosis selectively increases action potential-induced Ca2+ influx in epicardial myocytes of the rat left ventricle.

A decrease of the transient outward potassium current (Ito) has been observed in cardiac hypertrophy and contributes to the altered shape of the action potential (AP) of hypertrophied ventricular myocytes. Since the shape and duration of the ventricular AP are important determinants of the Ca2+ influx during the AP (QCa), we investigated the effect of ascending aortic stenosis (AS) on QCa in endo- and epicardial myocytes of the left ventricular free wall using the AP voltage-clamp technique. In sham-operated animals, QCa was significantly larger in endocardial compared to epicardial myocytes (803 +/- 65 fC pF(-1), n = 27 vs.