Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials

Abstract

The uterus and heart share the important physiological feature whereby contractile activation of the muscle tissue is regulated by the generation of periodic, spontaneous electrical action potentials (APs). Preterm birth arising from premature uterine contractions is a major complication of pregnancy and there remains a need to pursue avenues of research that facilitate the use of drugs, tocolytics, to limit these inappropriate contractions without deleterious actions on cardiac electrical excitation. A novel approach is to make use of mathematical models of uterine and cardiac APs, which incorporate many ionic currents contributing to the AP forms, and test the cell-specific responses to interventions. We have used three such models—of uterine smooth muscle cells (USMC), cardiac sinoatrial node cells (SAN), and ventricular cells—to investigate the relative effects of reducing two important voltage-gated Ca currents—the L-type (ICaL) and T-type (ICaT) Ca currents. Reduction of ICaL (10%) alone, or ICaT (40%) alone, blunted USMC APs with little effect on ventricular APs and only mild effects on SAN activity. Larger reductions in either current further attenuated the USMC APs but with also greater effects on SAN APs. Encouragingly, a combination of ICaL and ICaT reduction did blunt USMC APs as intended with little detriment to APs of either cardiac cell type. Subsequent overlapping maps of ICaL and ICaT inhibition profiles from each model revealed a range of combined reductions of ICaL and ICaT over which an appreciable diminution of USMC APs could be achieved with no deleterious action on cardiac SAN or ventricular APs. This novel approach illustrates the potential for computational biology to inform us of possible uterine and cardiac cell-specific mechanisms. Incorporating such computational approaches in future studies directed at designing new, or repurposing existing, tocolytics will be beneficial for establishing a desired uterine specificity of action.

Metabolic demand regulates selective cell death in Parkinson’s Disease

“…By changing this parameter, the electrophysiological properties were changed from that of the Substantia Nigra pars Compacta to that of the Ventral Tegmental Area. In addition, while SNc neurons and VTA neurons are both dopaminergic they differ in their subcellular processes and ion concentrations, specifically Ca 2+ [2] . The maximal conductance of the calcium channel of the SNc neuron was 2101.2 pA/mM.…”

“…Figure 2 Average resting membrane potential of VTA neurons from NeuroElectro Next, we reduced maximal conductance of the L-type calcium channel (G Ca ) by a scaling factor between 0 and 1, as done previously 2 . Maximal conductance is a measure of how easily an electrical current can pass through the channel.…”

Mathematical modeling of the female reproductive system: from oocyte to delivery

“…This provides detailed information on cell behavior but makes scaling of the model to multiple cells or ultimately the whole uterus computationally difficult. This complex mathematical model has been used, in conjunction with models of cardiac cells, to investigate the cell‐specific effects of tocolytics (anti‐contraction medication used to supress premature labor) . These drugs should target uterine smooth muscle cells and avoid influencing cardiac function, and the authors highlight the importance of computational models to test drug actions in silico prior to clinical trials.…”

“…This complex mathematical model has been used, in conjunction with models of cardiac cells, to investigate the cell-specific effects of tocolytics (anti-contraction medication used to supress premature labor). 87 These drugs should target uterine smooth muscle cells and avoid influencing cardiac function, and the authors highlight the importance of computational models to test drug actions in silico prior to clinical trials. The model has recently been improved to account for long duration bursting action potentials characteristic of labor, 88 and extended to a network of cells.…”

High-Throughput Screening of Myometrial Calcium-Mobilization to Identify Modulators of Uterine Contractility

“…Current research tools used for small-scale discovery or testing of tocolytics and uterotonics have utilized either: 1) computational modeling [ 16 , 17 ], 2) fluorescence-based Ca 2+ -assay [ 18 – 20 ], 3) recording Ca 2+ -channel currents using whole-cell patch clamp technology [ 19 , 21 ], 4) collagen gel contraction assay [ 22 , 23 ], 5) oxytocin receptor (OTR) assays [ 24 ], 6) ex vivo measurements of myometrial tension/contractility [ 25 – 31 ] [formerly referred to as oxytocic bioassay [ 24 ]], or 7) in vivo measurements of intrauterine pressure [ 32 – 34 ]. However, to our knowledge there are no reports of large-scale screening for the discovery of new tocolytic or uterotonic compounds.…”