A mathematical model of Ca2+ dynamics in rat mesenteric smooth muscle cell: agonist and NO stimulation.

Description

  A mathematical model of calcium dynamics in vascular smooth muscle cell (SMC) was developed based
on data mostly from rat mesenteric arterioles. The model focuses on (a) the plasma membrane
electrophysiology; (b) Ca2+ uptake and release from the sarcoplasmic reticulum (SR); (c) cytosolic
balance of Ca2+, Na+, K+, and Cl- ions; and (d) IP3 and cGMP formation in response to norepinephrine
(NE) and nitric oxide (NO) stimulation. Stimulation with NE induced membrane depolarization and an
intracellular Ca2+ ([Ca2+]i) transient followed by a plateau. The plateau concentrations were mostly
determined by the activation of voltage-operated Ca2+ channels. NE causes a greater increase in [Ca2+]i
than stimulation with KCl to equivalent depolarization. Model simulations suggest that the effect of
[Na+]i accumulation on the Na+/Ca2+ exchanger (NCX) can potentially account for this difference.
Elevation of [Ca2+]i within a concentration window (150-300 nM) by NE or KCl initiated [Ca2+]i
oscillations with a concentration-dependent period. The oscillations were generated by the nonlinear
dynamics of Ca2+ release and refilling in the SR. NO repolarized the NE-stimulated SMC and restored low
[Ca2+]i mainly through its effect on Ca2+ activated K+ channels. Under certain conditions, (Na+)-(K+)-(ATPase)
inhibition can result in the elevation of [Na+]i and the reversal of NCX, increasing resting cytosolic and
SR Ca2+ content, as well as reactivity to NE. Blockade of the NCX's reverse mode could eliminate these
effects. We conclude that the integration of the selected cellular components yields a mathematical
model that reproduces, satisfactorily, some of the established features of SMC physiology. Simulations
suggest a potential role of intracellular Na+ in modulating Ca2+ dynamics and provide insights into the
mechanisms of SMC constriction, relaxation, and the phenomenon of vasomotion. The model will
provide the basis for the development of multi-cellular mathematical models that will investigate
microcirculatory function in health and disease. J Theor Biol. 2008 Jul 21;253(2):238-60

This code reproduces Fig. 6 showing effect of nitric oxide on Ca_i and V_m.

To enable agonist-induced oscillations, set k_leak = 5, otherwise k_leak = 1.
To remove desensitization to NE, set k_pG = 0.

Adam Kapela a, Anastasios Bezerianos b, Nikolaos M. Tsoukias a,
a Department of Biomedical Engineering, Florida International University, Miami, FL 33199, USA
b Department of Medical Physics, University of Patras, Patras, Greece

Figures: Effect of 1 mM nitric oxide(NO) on Vm (top) and [Ca2+]i (bottom) following NE stimulation (solid lines). Dashed red lines represent time period of NO addition and are shown for timing purposes only.

Equations

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