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

Lookup NU author(s): Dr Winnie Tong, Dr Iffath Ghouri, Professor Michael Taggart

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Tong WC, Ghouri I, Taggart MJ

Publication type: Article

Publication status: Published

Journal: Frontiers in Physiology

Year: 2014

Volume: 5

Pages: 399

Online publication date: 16/10/2014

Acceptance date: 26/09/2014

Date deposited: 27/01/2015

ISSN (electronic): 1664-042X

Publisher: Frontier Research Foundation

URL: http://dx.doi.org/10.3389/fphys.2014.00399

DOI: 10.3389/fphys.2014.00399

PubMed id: 25360118


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