Computational studies on urinary bladder smooth muscle: Modeling ion channels and their role in generating electrical activity

Urinary incontinence is the involuntary loss of urine that creates a social or hygiene problem, which has detrimental effects on quality of life. Detrusor smooth muscle instability is a major cause of Urinary Incontinence. Different ion channels within bladder detrusor smooth muscle play a role in generating electrical activities such as action potentials and synaptic depolarizations. The aim is to establish a computational model of sufficient biophysical detail to simulate detrusor action potential and thereby inform future experimental investigations of pathophysiological mechanisms governing normal and dysfunctional bladder activities. In line with recent experimental evidence, adapting the Hodgkin-Huxley formulation in the NEURON platform, we construct mathematical models for seven ionic currents of detrusor smooth muscle, where the magnitudes and kinetics of each ionic current are described by differential equations, in terms of maximal conductances, electro chemical gradients, and voltage-dependent activation/inactivation gating variables. These quantifications are validated by the reconstruction of individual experimental ionic currents obtained under voltage clamp. Our simulated action potential has been validated by comparing with experimental recordings and shows good correspondence in terms of amplitude and shape. In summary, this mathematical model contributes an elemental tool to investigate the physiological ionic mechanisms underlying the spikes in detrusor smooth muscle, which in turn can shed light on genesis of bladder overactivity manifested in a malfunction.