A biophysically constrained computational model of the action potential of mouse urinary bladder smooth muscle

Abstract

Urinary incontinence is associated with enhanced spontaneous phasic contractions of the detrusor smooth muscle (DSM). Although a complete understanding of the etiology of these spontaneous contractions is not yet established, it is suggested that the spontaneously evoked action potentials (sAPs) in DSM cells initiate and modulate the contractions. In order to further our understanding of the ionic mechanisms underlying sAP generation, we present here a biophysically detailed computational model of a single DSM cell. First, we constructed mathematical models for nine ion channels found in DSM cells based on published experimental data: two voltage gated Ca ²⁺ ion channels, an hyperpolarization-activated ion channel, two voltage-gated K ⁺ ion channels, three Ca ²⁺-activated K ⁺ ion channels and a non-specific background leak ion channel. The ion channels’ kinetics were characterized in terms of maximal conductances and differential equations based on voltage or calcium-dependent activation and inactivation. All ion channel models were validated by comparing the simulated currents and current-voltage relations with those reported in experimental work. Incorporating these channels, our DSM model is capable of reproducing experimentally recorded spike-type sAPs of varying configurations, ranging from sAPs displaying after-hyperpolarizations to sAPs displaying after-depolarizations. The contributions of the principal ion channels to spike generation and configuration were also investigated as a means of mimicking the effects of selected pharmacological agents on DSM cell excitability. Additionally, the features of propagation of an AP along a length of electrically continuous smooth muscle tissue were investigated. To date, a biophysically detailed computational model does not exist for DSM cells. Our model, constrained heavily by physiological data, provides a powerful tool to investigate the ionic mechanisms underlying the genesis of DSM electrical activity, which can further shed light on certain aspects of urinary bladder function and dysfunction.