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

作者：Karlin Arthur^*

来源：Journal of General Physiology, 2015, 146(1): 79-96.

DOI：10.1085/jgp.201511380

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 Ca2+ concentration (Ca-in) within minutes of a change in pressure are the results of two opposing pathways, both of which use Ca2+ as a signal. This works because the two Ca2+-signaling pathways are confined to distinct microdomains in which the Ca2+ concentrations needed to activate key channels are transiently higher than Ca-in. 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 Ca2+-activated K+ (BK) channels. These junctional microdomains promote hyperpolarization, reduced Ca-in, and relaxation. The second type is postulated to form around stretch-activated nonspecific cation channels and neighboring Ca2+-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 alpha- and beta-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 V-m 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 Ca2+ channels on V-m and Ca-in. Deletion of BK beta 1 subunits is known to increase arterial-SM tension. In the model, deletion of beta 1 raised Ca-in at all pressures, and these increases were reversed by NO.

• 出版日期2015-7