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Background Although atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide. Objective The purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs. Methods The sodium channel blocking effects of propafenone (300 nM, 1 μM), flecainide (1 μM), and dronedarone (5 μM, 10 μM) were measured in human stem cell–derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c. Results A more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/– hearts, which have a more positive RMP compared to wild type. Conclusion Atrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.

This paper provides a review of approaches to delivering locally led adaptation. Drawing on examples from Africa, the Asia-Pacific region, and the Caribbean and Latin America, it provides practical recommendations for financing and implementing locally led adaptation. It helps demystify the steps funders and governments can take to ensure local partners have equitable access to climate finance and are at the center of decision-making processes.

The large conductance voltage and calcium activated potassium (BK) channels play a crucial role in regulating the excitability of detrusor smooth muscle, which lines the wall of the urinary bladder. These channels have been widely characterized in terms of their molecular structure, pharmacology and electrophysiology. They control the repolarising and hyperpolarising phases of the action potential, thereby regulating the firing frequency and contraction profiles of the smooth muscle. Several groups have reported varied profiles of BK currents and I-V curves under similar experimental conditions. However, no single computational model has been able to reconcile these apparent discrepancies. In view of the channels' physiological importance, it is imperative to understand their mechanistic underpinnings so that a realistic model can be created. This paper presents a computational model of the BK channel, based on the Hodgkin-Huxley formalism, constructed by utilising three activation processes - membrane potential, calcium inflow from voltage-gated calcium channels on the membrane and calcium released from the ryanodine receptors present on the sarcoplasmic reticulum. In our model, we attribute the discrepant profiles to the underlying cytosolic calcium received by the channel during its activation. The model enables us to make heuristic predictions regarding the nature of the sub-membrane calcium dynamics underlying the BK channel's activation. We have employed the model to reproduce various physiological characteristics of the channel and found the simulated responses to be in accordance with the experimental findings. Additionally, we have used the model to investigate the role of this channel in electrophysiological signals, such as the action potential and spontaneous transient hyperpolarisations. Furthermore, the clinical effects of BK channel openers, mallotoxin and NS19504, were simulated for the detrusor smooth muscle cells. Our findings support the proposed application of these drugs for amelioration of the condition of overactive bladder. We thus propose a physiologically realistic BK channel model which can be integrated with other biophysical mechanisms such as ion channels, pumps and exchangers to further elucidate its micro-domain interaction with the intracellular calcium environment.

The current study investigates the interplay between two important regulatory cellular signals that control contractions in the muscle, namely, intracellular calcium concentration and ATP. In this work, we have attempted to study how two regulatory signals interplay to affect the contractile responses of the muscle. The action of ATP hinders the myosin and actin from binding to each other, whereas, the effect of intracellular calcium mediates their cross-linkages. Thus, the study of two opposing signals and the effect of their interplay on the filament properties as well as on the contractile responses have been studied here. The Hai and Murphy contraction model has been modified to perform the current study. The ATP dependency was introduced into this model and through our simulations, we were able to demonstrate the importance of incorporating the same. Our model was able to reproduce physiologically realistic contraction profiles and stress values that befits a smooth muscle. Further, we used our model to estimate duty ratio and sliding velocity for the filament, under normal, loaded and pathological conditions.

This paper employs a computational model to study the dual gating modalities of BK channels in smooth muscles. These channels are gated by both membrane potential and intracellular calcium concentration. It has been previously reported that the sensors for these two stimuli are located at different regions of the channel. Thus, the two sensing modalities act independent of each other. Yet, they result in a concerted and synergistic opening of the channel pore. In this paper, we investigate the effects of these two gating mechanisms by computing the effective gating charges contributed by the channel's voltage and calcium sensors. Along with their independent contributions, we study and estimate the interplay and effect of these two modalities on the channel's activation. The voltage and calcium sensors appear to share the 'load' of the gating charges required to activate the channel based on the cytosolic calcium concentration and membrane potential. Thus, through our computational model, we demonstrate how the two independent sensors gate and coordinate the activation of the channel.

Ion channels are molecular entities that are responsible for electrical signal generation in nerve, muscle and other cells. The paper discusses the use of tangent hyperbolic functions (TANH) in the modelling of the Big Conductance Potassium (BK) ion channel, especially for the smooth muscle of the urinary bladder. Ion channels are often modelled using the Hodgkin-Huxley formalism, in which equations governing the dependencies of various state parameters on cellular variables are derived from experimental data. When there is sufficient experimental data, formulating equations that replicate the trend becomes relatively easy. However, where the data for these dependencies is sparse, usual approaches fail. Here, we describe a TANH spline interpolation technique as an efficient means of fitting sparse data. TANH is used to "braid" functions in two adjacent regions and is done, unlike with splines, in a way such that a single function operates over the whole region. The resultant function is whole range, continuous and differentiable to any arbitrary order. We have demonstrated the application of this technique in modelling the parameter "slope factor" for the BK channel of mammalian smooth muscle. We show that, by the use of this technique, BK channel current outputs thus generated, faithfully replicate physiologically recorded BK currents from the detrusor smooth muscles of guinea-pig bladder. We propose this method as one of the general application in modelling ion channels constrained by sparse experimental data.