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.
Highlights
Computational modeling of an action potential (AP) of an electrically excitable cell was first developed in 1952 with the landmark study of neurons (Hodgkin and Huxley, 1952)
When we traced back the original formulation of this ICaT to Zeng et al (1995), and the experimental values from which its kinetics details were based to Droogmans and Nilius (1989), we did not find any typographical errors in the model equations or the experimental values to explain the discrepancy
Our approach can be regarded as a useful platform to be built upon for assessing the potential of tocolytics that act upon ion channels or electrogenic ion exchangers
Summary
Computational modeling of an action potential (AP) of an electrically excitable cell was first developed in 1952 with the landmark study of neurons (Hodgkin and Huxley, 1952). Many computational models exist to describe in considerable detail cardiac cell-specific excitation-contraction properties, including the biophysical details of the constituent ion currents and calcium fluxes. These include multicellular tissue and organ maps of spatiotemporal electrical and calcium wave propagation (Rudy, 2000; Zhang et al, 2000; Kleber and Rudy, 2004; Severi et al, 2009; Aslanidi et al, 2011b; Atkinson et al, 2011). Mathematical models are continuously being developed and applied to predicting the risks of pathophysiological phenomena (e.g., the likelihood of dyssynchronous activation and fibrillation) (Benson et al, 2008; Bishop and Plank, 2012; Cherry et al, 2012; Kharche et al, 2012; Behradfar et al, 2014) as well as the potential beneficial effects of drugs and treatments (Levin et al, 2002; Muzikant and Penland, 2002; Davies et al, 2012; Mirams et al, 2012; di Veroli et al, 2013, 2014)
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