Cell models, cardiac

Adriamycin is completely without effect on cell proliferation in severely iron-deficient Euglena gracilis and has substantially diminished activity in the Fe-deficient mammalian HL-60 tumor and H9c2 (2-1) heart myoblast cell lines. ° Thus, the availability of cellular iron is necessary for much, if not all, of the cytotoxic effects of Adr in tumor and cardiac cell models. 

The reasons for this are diverse and include the fact that models of cardiac cellular activity were among the first cell models ever developed. Analytical descriptions of virtually all cardiac cell types are now available. Also, the large-scale integration of cardiac organ activity is helped immensely by the high degree of spatial and temporal regularity of functionally relevant events and structures, as cells in the heart beat synchronously. 

Cardiac models are amongst the most advanced in silico tools for bio-med-icine, and the above scenario is bound to become reality rather sooner than later. Both cellular and whole organ models have aheady matured to a level where they have started to possess predictive power. We will now address some aspects of single cell model development (the cars ), and then look at how virtual cells interact to simulate the spreading wave of electrical excitation in anatomically representative, virtual hearts (the traffic ). 

In contrast to the pre-existing models that merely portrayed membrane potentials, the new generation of models calculated the ion fluxes that give rise to the changes in cell electrical potential. Thus, the new models provided the core foundation for a mechanistic description of cell function. Their concept was applied to cardiac cells by Denis Noble in 1960. 

These detailed cell models can be used to study the development in time of processes like myocardial ischaemia (a reduction in coronary blood flow that causes under-supply of oxygen to the cardiac muscle), or effects of genetic mutations on cellular electrophysiology. They allow to predict the outcome of changes in the cell s environment, and may even be used to assess drug actions. 

These may be produced by grouping together multiple cell models to form virtual tissue segments, or even the whole organ. The validity of such multi-cellular constructs crucially depends on whether or not they take into account the heart s fine architecture, as cardiac structure and function are tightly interrelated. 

As indicated above, theoretical models for biological rhythms were first used in ecology to study the oscillations resulting from interactions between populations of predators and preys [6]. Neural rhythms represent another field where such models were used at an early stage The formalism developed by Hodgkin and Huxley [7] stiU forms the core of most models for oscillations of the membrane potential in nerve and cardiac cells [33-35]. Models were subsequently proposed for oscillations that arise at the cellular level from regulation of enzyme, receptor, or gene activity (see Ref. 31 for a detailed fist of references). 

Meyer, T, Sartipy P., Blind, F., Leisgen, C. and Guenther, E. (2007) New cell models and assays in cardiac safety profiling. Expert Opinion on Drug Metabolism and Toxicology, 3 (4), 507—517. 

Apart from its potent antiproliferative activity, tetrasaccharide 15 was effective in blocking human complement in vitro and inhibited the release of heparan sulfate from cardiac microvascular endothelial cells. To overcome hyperacute rejection, the tetrasaccharide has been investigated in a guinea pig to rat cardiac xenotransplantation model and significantly prolonged the survival of heart recipients when compared to control and heparin treated groups [46]. 

The precise mechanism and sight of action of most compounds categorized as calcium inhibitory compounds, therefore, remains obscure. Future refinements in experimental models and techniques will undoubtedly will lead to the classification of calcium inhibitory compounds based upon their primary mechanism of action and specific site(s) of action (extracellular vs. intracellar). Because of the uncertainty surrounding the precise mechanisms of action of calcium inhibitory compounds, I will describe their cardiac electrical and mechanical effects illuding when possible to those compounds that are believed to act l) competitively with Ca + for specific calcium channels (e.g., Co +, Mn +, La2+, etc.) 2) at the cardiac cell membrane and possibly by one of several intracellular mechanisms (e.g., verapamil, diltiazem, nifedipine) and 3) intracellularly (e.g., 2-n-propyl and 2-n-butyl MDI). 

The last part of chapter 9 is devoted to a study of intracellular Ca waves. Computer simulations show that the model based on CICR can account for the two types of wave seen in the experiments in different cell types (Dupont Goldbeter, 1992b, 1994). When the period of the oscillations is of the order of 1 s, as in cardiac cells, the wave takes the... 

The waveform of the oscillations predicted by the model for cytosolic Ca (fig. 9.7) resembles that of the spikes observed for a number of cells stimulated by external signals. In particular, the rise in cytosolic Ca is preceded by a rapid acceleration that starts from the basal level although it originates from a different, nonelectrical mechanism, this pattern, which is reminiscent of the pacemaker potential that triggers autonomous spiking in nerve and cardiac cells (DiFrancesco, 1993), has been observed (Jacob et al, 1988) in epithelial cells stimulated by histamine (see fig. 9.3). As in the model by Meyer Stryer (1988), the oscillations of Ca " in the intracellular store have a saw-tooth appearance (see the dashed ctirve in fig. 9.7). Here, however, the phenomenon does... 

Functional cell-based cardiac Isolated primary cardiac cells from CPGC showed intraluminal The model may provide a Birla et al. 

Davis, R.R, van den Berg, C.W., Casini, S., Braam, S.R., and Mummery, C.L. (2011) Pluripotent stem cell models of cardiac disease and their implication for drug discovery and development. Trends Mol. Med. 17, 475 84. 

CORM-3 protected cardiac cells against hypoxia and reperfusion, as well as limited infarct size in hearts following ischemic insult [32]. In a mice model of heart ischemia and reperfusion (coronary occlusion/reperfusion), CORM-3 promoted similar cardioprotective effects, via decreasing the apoptotic markers, such as cleaved lamin, cleaved caspase-3, and cleaved PARP-1 [77]. CORM-2 also presented cardioprotective effects against myocardial ischemia-reperfusion [78] and doxorubicin-induced cardiotoxicity, which has been a drug used in human malignancies for decades [79]. 

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