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 From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: currents (L- and T-type), current, an hyperpolarization-activated current, three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.
Highlights
For over 50 years it has been known that uterine smooth muscle generates spontaneous action potentials (APs) [1,2,3]
Detailed formulations of individual model components are given in Appendix S1
L-type Calcium current – ICaL Mathematical descriptions of the biophysical characteristics of this current are given in Appendix S1
Summary
For over 50 years it has been known that uterine smooth muscle (myometrium) generates spontaneous action potentials (APs) [1,2,3]. Information on how these individual ionic currents are integrated to form the shape and timecourse of APs reflective of those reported for the myometrium is sparse This severely limits the ability to model simultaneous changes in myometrial membrane potential, 1⁄2Ca2zi and force that are the essential elements of electrical E-C coupling. To develop biophysically detailed quantitative (mathematical) descriptions of all known individual ionic currents of uterine smooth muscle cells pertaining to near the end of pregnancy. To compute these, in alliance with descriptions of dynamic Ca2z handling parameters, into a mathematical model of myometrial action potential generation To extend this model to the simulation of concomitant recordings of spontaneous AP, Ca2z and force in uterine smooth muscle. It provides a framework of relevance for exploring the biophysical modeling of individual ionic currents underlying the electrogenic processes in other smooth muscles, tissues and organs
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