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A computational model of the ionic currents, Ca2+ dynamics and action potentials underlying contraction of isolated uterine smooth muscle.

ABSTRACT: Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: Ca2+ currents (L- and T-type), Na+ current, an hyperpolarization-activated current, three voltage-gated K+ currents, two Ca2+-activated K+ current, Ca2+-activated Cl current, non-specific cation current, Na+-Ca2+ exchanger, Na+-K+ pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area:volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular Ca2+ computed from known Ca2+ fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing [Ca2+]i. This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes), the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, [Ca2+]i and phasic force. In summary, our advanced mathematical model provides a powerful tool to investigate the physiological ionic mechanisms underlying the genesis of uterine electrical E-C coupling of labor and parturition. This will furnish the evolution of descriptive and predictive quantitative models of myometrial electrogenesis at the whole cell and tissue levels.

SUBMITTER: Tong WC

PROVIDER: S-EPMC3084699 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A computational model of the ionic currents, Ca2+ dynamics and action potentials underlying contraction of isolated uterine smooth muscle.

Tong Wing-Chiu WC Choi Cecilia Y CY Kharche Sanjay S Holden Arun V AV Zhang Henggui H Taggart Michael J MJ

PloS one 20110429 4

Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C c ...[more]

PMID: 21559514

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Project description:Pulmonary veins (PVs) and the coronary sinus (CS) play pivotal roles in triggering some episodes of atrial fibrillation. In isolated rabbit right or left atrial preparations, a 3-hour intermittent burst pacing protocol shortens action potential duration (APD) in CS and PV, but not in sinus node (SN) and left Bachmann bundle (BB) regions.The purpose of this study was to use patch clamp techniques to study the rapidly inactivating (I(to)) and sustained (I(sus)) K(+) currents as well as Ca(2+) currents (I(Ca)) in cells dispersed from intermittent burst pacing and sham PV, BB, CS, and SN regions to determine whether changes in these currents contributed to APD shortening.Real-time polymerase chain reaction was performed for transient outward K(+) and Ca(2+) channel subunit mRNAs to determine if intermittent burst pacing affected expression levels.I(to) densities were unaffected by intermittent burst pacing in PV and Bachmann bundle cells. mRNA levels of K(V)4.3, K(V)4.2, K(V)1.4, and KChIP2 subunits of I(to) in both regions were stable. In CS cells, I(to) densities in intermittent burst pacing were greater than in sham (P <.05), but there were no parallel mRNA changes. I(Ca) density of PV cells was reduced from 14.27 +/- 2.08 pA/pF (at -5 mV) in sham to 7.52 +/- 1.65 pA/pF in intermittent burst pacing PV cells (P <.05) due to a significant shift in voltage dependence of activation. These results were seen in the absence of mRNA changes in alpha(1C) and alpha(1D) Ca(2+) channel subunits. In contrast, intermittent burst pacing had no effect on Ca(2+) current densities and kinetics of CS cells, but decreased alpha(1)C and alpha(1)D mRNA levels.There is region-specific remodeling of I(to) and I(Ca) by intermittent burst pacing protocols in rabbit atrium. Increased I(to) in CS cells could account for the APD shortening observed with intermittent burst pacing, whereas an intermittent burst pacing-induced shift in voltage dependence of activation may contribute to APD shortening in PV cells.

Project description: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.

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A computational model of the ionic currents, Ca2+ dynamics and action potentials underlying contraction of isolated uterine smooth muscle.

Publications

A computational model of the ionic currents, Ca2+ dynamics and action potentials underlying contraction of isolated uterine smooth muscle.

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