A mathematical model of Ca2+ dynamics in rat mesenteric smooth muscle cell: agonist and NO stimulation.
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.
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Kapela A, Bezerianos A, Tsoukias NM.: A mathematical model of Ca2+ dynamics in rat mesenteric smooth muscle cell: agonist and NO stimulation, J Theor Biol 253:238-260, 2008 Silva HS, Kapela A, Tsoukias NM: A mathematical model of plasma membrane electrophysiology and calcium dynamics in vascular endothelial cells. Am J Physiol Cell Physiol 293:C277-C293, 2007 Kapela A, Bezerianos A, Tsoukias NM: A mathematical model of vasoreactivity in rat mesenteric arterioles: I. Myoendothelial communication, MICROCIRC 16:8,(694-U69), 2009
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