Development of a multi-dimensional computational model of the rat uterus for the study of contractile synchronicity

The mammalian uterus plays a central role in the reproductive process. During pregnancy the organ undergoes a process of remodelling that is not restricted to a change in volume; its behaviour transitions from relative quiescence to regular contraction. This progression is incompletely understood; in particular, questions surround the final stages when the organ transitions from a non-labouring state to a labouring state and complications such as pre-term birth can occur. Pre-term birth is associated with an increased chance of morbidity and mortality for the child and is the leading cause of death in children under 5 worldwide. Up to 13% of births in the developed world are pre-term and the annual cost to society of managing this problem is considerable; in 2006 the financial cost was estimated to be over £2.9 billion in England and Wales alone. In this project a physiologically detailed, multi-dimensional, computational model of the rat uterus, which scales from the single-cell up to a full 3D organ, was developed and used to investigate uterine function. The single-cell model incorporates several changes from the previously published Tong et al 2011 model. The present model includes alternative descriptions of the intracellular ion handling and mechanical systems of the uterine cell, in addition to a reformulated L-Type calcium current, voltage-activated potassium current, calcium-activated potassium current and calcium-activated chloride current. The hypothesis that sodium-channel density can act as a trigger mechanism for initiating labour in late pregnancy was explored. The present model is able to accurately predict and reproduce calcium transients based on experimental patch clamp recordings, as well as the effects of drugs and hormones, including oestradiol, oxytocin, wortmannin and nifedipine. The model was used to investigate the adverse effects of using nifedipine as a tocolytic agent on the cardiovascular system and suggest countermeasures that could permit its use in patients with pre-existing heart conditions: using agonists that target the sodium-potassium pump and SERCA to partially restore vascular function, without impeding nifedipine's tocolytic efficacy. A tissue model was then constructed and used to investigate the synchronisation of electrical activity in myometrial tissue. The primary hypothesis was that heterogeneities within the tissue could evoke the spontaneous and sustained activity required for synchronicity. It was shown that spatial heterogeneity in electrical coupling played an important role in sustaining electrical activity. Spontaneous activity was evoked by using a tissue sample containing cells with heterogeneous excitability, resulting from a stochastic element in the activation potential of their sodium-channels. It was shown that at least 3% - 8% of cells must be pacemaking in order to produce stable electrical waves that propagate successfully in tissue. This work represents an advance in comprehensive uterine cell modelling and extends considerations beyond purely deterministic models, towards models that include stochastic elements, which can uncover complex, non-linear behaviours of uterine electrophysiological systems.