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Denis Noble

Publications and source records attributed to Denis Noble.

26 records · Page 2Linked to original sources
PubMed2002

Modeling the heart--from genes to cells to the whole organ.

Successful physiological analysis requires an understanding of the functional interactions between the key components of cells, organs, and systems, as well as how these interactions change in disease states. This information resides neither in the genome nor even in the individual proteins that genes code for. It lies at the level of protein interactions within the context of subcellular, cellular, tissue, organ, and system structures. There is therefore no alternative to copying nature and computing these interactions to determine the logic of healthy and diseased states. The rapid growth in biological databases; models of cells, tissues, and organs; and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way from the level of genes to the physiological function of whole organs and regulatory systems. This review illustrates this development in the case of the heart. Systems physiology of the 21st century is set to become highly quantitative and, therefore, one of the most computer-intensive disciplines.

Animals↗
PubMed2002

Modelling the heart: insights, failures and progress.

Mathematical models of the heart have developed over a period of about 40 years. Cell types in all regions of the heart have been modelled and they are now being incorporated into anatomically detailed models of the whole organ. This combination is leading to the creation of the first 'virtual organ,' which is being used in drug discovery and testing, and in simulating the action of devices, such as cardiac defibrillators. Simulation is a necessary tool of analysis in attempting to understand biological complexity. We often learn as much from the failures as from the successes of mathematical models. It is the iterative interaction between experiment and simulation that is important. Examples are given where this process has been instrumental in some of the major advances in the field.

Animals↗
PubMed2002

The rise of computational biology.

The year 2001 saw a remarkable burst of interest in biological simulation, with several international meetings on the subject, and the inclusion, by journals, of web site references from which published models can be downloaded. So, why has all this happened so suddenly?

Animals↗
PubMed2002

Analysis of the chronotropic effect of acetylcholine on sinoatrial node cells.

INTRODUCTION: The ionic basis underlying the negative chronotropic effect of acetylcholine (ACh) on sinoatrial (SA) node cells is unresolved and controversial. In the present study, mathematical modeling was used to address this issue. METHODS AND RESULTS: The known concentration-dependent effects of ACh on iK,ACh, iCa,L, and i(f) were introduced into models of rabbit central and peripheral SA node cells. In the central and peripheral models, 9 x 10(-8) and 14 x 10(-8) M ACh, respectively, caused a 50% decrease in pacemaking rate, whereas in rabbit SA node to approximately 7.4 x 10(-8) M ACh caused such a decrease. In the models, iK,ACh was primarily responsible for the decrease and actions of ACh on iCa,L or i(f) alone caused a negligible effect. Although the inhibition of i(f) did not directly contribute to the chronotropic effect, it was indirectly important, because it minimized the opposition by i(f ) to the decrease of rate caused by activation of iK,ACh. The central model was more sensitive to ACh than the peripheral model. CONCLUSION: The chronotropic effect of ACh is principally the result of activation of iK,ACh, and inhibition of iCa,L plays little or no role. Inhibition of i(f) and possible inhibition of ib,Na play an important facilitative role by reducing the ability of i(f) and ib,Na to curtail the chronotropic effect caused by activation of iK,ACh.

Acetylcholine↗
PubMed2002

Influence of Na/Ca exchange stoichiometry on model cardiac action potentials.

Cardiac action potential simulations were done with the stoichiometry of the Na/Ca exchanger set a 4: 1. Using the Hilgemann-Noble (1987) model, this stoichiometry reduces the resting potential unless regulation by intracellular calcium is incorporated. The K(d) required for such regulation is consistent with current experimental estimates of this parameter.

Action Potentials↗
PubMed2002

Simulation of Na/Ca exchange activity during ischemia.

Simulation of sodium-calcium exchange activity during the rise of intracellular sodium that occurs during ischemia suggests that the exchanger may not reverse direction except transiently during calcium oscillations. This conclusion depends on the presence of a small resting leak of calcium into the cell, consistent with radioactive calcium flux measurements. The conditions for intracellular calcium to rise to around 3 microM were explored. A combination of extracellular potassium accumulation and extracellular sodium depletion is sufficient to explain this result. The computations also show a counterintuitive result concerning the role of the exchanger in the mechanism of calcium oscillations. Reducing its activity would be expected to enhance these oscillations, whereas increasing it can reduce or suppress oscillations. If such oscillations play a role in acute ischemic arrhythmias, then block of Na/Ca exchange may not be therapeutic.

Animals↗
PubMed2002

The heart cell in silico: successes, failures and prospects.

The development of computer models of heart cells is used to illustrate the interaction between simulation and experimental work. At each stage, the reasons for new models are explained, as are their defects and how these were used to point the way to successor models. As much, if not more, was learnt from the way in which models failed as from their successes. The insights gained are evident in the most recent developments in this field, both experimental and theoretical. The prospects for the future are discussed.

Animals↗