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Membrane potential and Ca2+ concentration dependence on pressure and vasoactive agents in arterial smooth muscle: A model

Karlin, Arthur

Arterial smooth muscle (SM) cells respond autonomously to changes in intravascular pressure, adjusting tension to maintain vessel diameter. The values of membrane potential (V_m) and sarcoplasmic Ca^2+ concentration (Ca_in) within minutes of a change in pressure are the results of two opposing pathways, both of which use Ca^2+ as a signal. This works because the two Ca^2+-signaling pathways are confined to distinct microdomains in which the Ca^2+ concentrations needed to activate key channels are transiently higher than Cain. A mathematical model of an isolated arterial SM cell is presented that incorporates the two types of microdomains. The first type consists of junctions between cisternae of the peripheral sarcoplasmic reticulum (SR), containing ryanodine receptors (RyRs), and the sarcolemma, containing voltage- and Ca^2+-activated K^+ (BK) channels. These junctional microdomains promote hyperpolarization, reduced Cain, and relaxation. The second type is postulated to form around stretch-activated nonspecific cation channels and neighboring Ca^2+-activated Cl^− channels, and promotes the opposite (depolarization, increased Ca_in, and contraction). The model includes three additional compartments: the sarcoplasm, the central SR lumen, and the peripheral SR lumen. It incorporates 37 protein components. In addition to pressure, the model accommodates inputs of α- and β-adrenergic agonists, ATP, 11,12-epoxyeicosatrienoic acid, and nitric oxide (NO). The parameters of the equations were adjusted to obtain a close fit to reported Vm and Ca_in as functions of pressure, which have been determined in cerebral arteries. The simulations were insensitive to ±10% changes in most of the parameters. The model also simulated the effects of inhibiting RyR, BK, or voltage-activated Ca^2+ channels on V_m and Ca_in. Deletion of BK β1 subunits is known to increase arterial–SM tension. In the model, deletion of β1 raised Ca_in at all pressures, and these increases were reversed by NO.


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Also Published In

The Journal of General Physiology

More About This Work

Academic Units
Biochemistry and Molecular Biophysics
Published Here
August 10, 2015