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Sources of Funding: none

Introduction

Detrusor instability is characterized by sudden involuntary contraction of the detrusor smooth muscle (DSM) cells. In various smooth muscle cells, inward rectifying channel Ih has been playing an important role in regulating resting membrane potential (RMP) and basal tone. Therefore, a detailed biophysical study of Ih channel is essential to investigate DSM cell&[prime]s excitability towards detrusor instability. This current study aims to model Ih channel in DSM cells to analyze its&[prime] modulating effects in internal spontaneous myogenic electrical activities.

Methods

The DSM cell membrane is represented as a parallel resistor-capacitor circuit consisting of a membrane capacitance Cm and a variable Ih ion channel conductance g_h. The voltage-gated Ca2+ and K+ channels, Ca2+ activated K+ channels and leakage currents are incorporated from a published model to generate electrical activities. In this model, Hodgkin-Huxley formalism is adapted for Ih ionic currents with parameters from literature.

Results

The RMP is set at -50 mV to mimic the experimental value in mouse DSM cell. The maximum conductance of Ih channel is set at 0.0002 mho/cm² to generate the action potential (AP) shown in figure (Blue line) by inducing synaptic input to mimic effects of purinergic neurotransmitter. By reducing the maximum conductance to 0.00016 mho/cm², DSM cell couldn&[prime]t generate any AP (black line in figure) as the cell is unable to open transient Ca²⁺ channels. However, higher activation time constant causes the AP (red line) with the higher peak and slower after hyperpolarization compared to control AP (blue line). The AP (red line) is generated early due to faster activation and early crossing of the threshold value.

Conclusions

The reduction of Ih channel conductance and activation time constant result hyperpolarization, slower afterhyperpolarization and a consequent reduction in DSM cell&[prime]s excitability. Presently, researchers are focusing much effort on developing novel compounds acting through different ways to minimize the severe side effects of anticholinergic agents like trospium chloride and oxybutynin. As the Ih channel blockers hyperpolarize the DSM cell, the pharmacological targeting of these channels may play a dominant role for treatment of detrusor instability.

Funding

none