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.
Kapela
Adam
A
Department of Biomedical Engineering, Florida International University, Miami, FL 33199, USA. akapela@fiu.edu
Bezerianos
Anastasios
A
Tsoukias
Nikolaos M
NM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008643:Mesentery / Q000098:blood supply; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
D002118:Calcium; D015220:Calcium Channels; D009569:Nitric Oxide; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D000097795:ATPase Inhibitory Protein