MODULATING EFFECTS OF CASTRATION ON VAS DEFERENS SMOOTH MUSCLE ELECTRICAL ACTIVITIES: INSIGHTS FROM A QUANTITATIVE STUDY

Abstract

The vas deferens smooth muscle (VDSM), which is dependent on testosterone, generates spontaneous contraction. Although the factors modulating the spontaneous contraction are not completely understood, different experimental studies have supported that the VDSM cell electrophysiological phenomena is eminently correlated to it. According to a recent study, the castration has down regulated the A-type K+ channel activities in VDSM cell [Ohya et al., 2019]. In the present time, computational modeling plays a powerful role in understanding various complex biological/physiological systems. To explore the quantitative contribution of castration into the VDSM membrane electrical activities, a biophysically detailed single VDSM cell model is presented. First, we constructed computational models for seven ion channels found in guinea-pig VDSM cells based on published experimental data: One voltage gated Na+ ion channel, two voltage gated Ca2+ ion channels, a hyperpolarization-activated ion channel, two voltage-gated K+ ion channels, one Ca2+-activated K+ ion channels and a nonspecific background leak ion channel. All ion channel models were validated by comparing the simulated currents and current-voltage relationship with those reported in experimental work. Then, all ion channels were integrated to simulate the VDSM electrical activities towards neurotransmitter/current stimulus. We investigated the contribution of the castration by mimicking the testosterone as down regulation of A-type K+ channel on VDSM cell excitability. The ion channel conductnaces are set to maintain the resting membrane potential (RMP) at — 50 mV as the physiological range of RMP in VDSM cell varies from — 45 mV to — 70 mV. The action potential (AP) and membrane depolarization are simulated in the whole cell model by applying an external stimulus current (10-30 pA), as a brief square pulse of 10 ms duration. The results showed both L-type Ca2+ and Na+ channel are indispensable for generating the spike, although the L-type Ca2+ channel is the major contributor to the total inward current. The results also revealed that both BK and A-type K+ channel channels are essential in maintaining the RMP and repolarization. Because of castration, A-type K+ current is reduced, and as a result, it elevated the RMP from — 50 mV to — 47 mV (more positive). The model was able to evoke an AP with a reduced current stimulus. To date, a biophysically detailed computational model does not exist for VDSM cells. Our model, constrained heavily by physiological data, provides a powerful tool to investigate the ionic mechanisms underlying the genesis of VDSM electrical activity. In the guinea-pig, following castration, VDSM was accompanied by cell membrane depolarization, which caused to evoke more spontaneous contractions.