A Computational Model of the Ionic Currents, Ca2+ Dynamics and Action Potentials Underlying Contraction of Isolated Uterine Smooth Muscle

Abstract

Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: currents (L- and T-type), current, an hyperpolarization-activated current, three voltage-gated currents, two -activated current, -activated current, non-specific cation current, - exchanger, - pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area∶volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular computed from known fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing . This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes), the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, and phasic force. In summary, our advanced mathematical model provides a powerful tool to investigate the physiological ionic mechanisms underlying the genesis of uterine electrical E-C coupling of labor and parturition. This will furnish the evolution of descriptive and predictive quantitative models of myometrial electrogenesis at the whole cell and tissue levels.

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells

“…Myometrial smooth muscle cells express transient receptor potential channels (52) and several classes of voltage-gated channels, including T-and L-type calcium channels (53)(54)(55). To examine the potential contribution of these channels, we used mibefradil, a non-selective, voltagegated calcium channel blocker (56), and SKF96365, a widely used inhibitor of transient receptor potential channels (57) which can also potently inhibit both L-and T-type calcium channels (58).…”

Modelling the Effects of Nifedipine on Ventricular and Myometrial Cells of Pregnant Rats

“…The ventricle cell is described by the Pandit et al model [4] and the myometrial cell by a modified Tong et al model [5]. Figure 1 shows the two cell models used, including each of the ion channels, pumps and exchangers.…”

Simulating uterine contraction by using an electro-chemo-mechanical model

“…The process which leads to AP generation can be replicated through a Hodgkin-Huxley-like model, see, e.g., (Hodgkin and Huxley 1952;Burdyga et al 2007;Tong et al 2011).…”

“…The total current defined in the Hodgkin-Huxley model then follows from conservation of charge for all ions entering and leaving the cell. The Hodgkin-Huxley model has been vastly used to explain the excitability of smooth muscle cell membranes (Victorri et al 1985;Tong et al 2011;Yang et al 2003;Toth et al 2013;Korogod and Kochenov 2013;Sharifimajd and Stål-hand 2014). The model is complex and computationally expensive, however.…”

“…Most of the published studies on uterine activity concern only the electrophysiology of the USMC membrane (Buhimschi et al 1997;Maul et al 2003;Burdyga et al 2007;Bursztyn et al 2007;Tong et al 2011;La Rosa et al 2012). The only study which has simulated uterine contraction is due to Cochran and Gao (2013).…”