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We developed a comprehensive cell model that simulates the sequential cellular events from membrane excitation to contraction in the human ventricle. By combining this ventricular cell model with a lumped circulation model, we examined how blood pressure dynamics in the ventricle and aorta are related to the cellular processes. To convert cell contraction into ventricular pressure using Laplace's law, we introduced a simple geometric model of a ventricle: one shaped like a thin-walled hemisphere. The force of contraction of a single cell induces tension in the hemispheric ventricular wall, which generates the ventricular and aortic pressures in the lumped circulation model. The time courses of the hemodynamic properties, as well as the volume-pressure trajectory of the left ventricle, were well reproduced. Our multi-scale cardiovascular model, which covers from cardiac cells to the circulatory system, simulates the typical characteristics of heart mechanics, such as the pressure-volume relationship, stroke volume and the effect of the increased maximum free calcium concentration on cardiovascular hemodynamics. To test the cell-circulation coupling characteristics of the model, we simulated the effects of a decrease in L-type calcium channel conductance (cell level) on left ventricular pressure (system level). The variation due to different pacing frequencies for myocyte excitation was also investigated to assess the effects of heart rate on cardiac cells and the circulatory system.

The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD) prolongation that involves increase in late L-type Ca2+ current (ICaL) caused by a decrease in Ca2+-dependent inactivation (CDI). Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies. [ABSTRACT FROM AUTHOR]

Cellular processes are exquisitely sensitive to H+ and Ca2+ ions because of powerful ionic interactions with proteins. By regulating the spatial and temporal distribution of intracellular [Ca2+] and [H+], cells such as cardiac myocytes can exercise control over their biological function. A well-established paradigm in cellular physiology is that ion concentrations are regulated by specialized, membrane-embedded transporter proteins. Many of these couple the movement of two or more ionic species per transport cycle, thereby linking ion concentrations among neighbouring compartments. Here, we compare and contrast canonical membrane transport with a novel type of Ca2+-H+ coupling within cytoplasm, which produces uphill Ca2+ transport energized by spatial H+ ion gradients, and can result in the cytoplasmic compartmentalization of Ca2+ without requiring a partitioning membrane. The mechanism, demonstrated in mammalian myocytes, relies on diffusible cytoplasmic buffers, such as carnosine, homocarnosine and ATP, to which Ca2+ and H+ ions bind in an apparently competitive manner. These buffer molecules can actively recruit Ca2+ to acidic microdomains, in exchange for the movement of H+ ions. The resulting Ca2+ microdomains thus have the potential to regulate function locally. Spatial cytoplasmic Ca2+-H+ exchange (cCHX) acts like a 'pump' without a membrane and may be operational in many cell types. [ABSTRACT FROM AUTHOR]

Abstract: This experimental study describes the fabrication and analysis of a micro-perfusion system that can be used in many bioengineering experiments to create rapid, large regional intracellular changes within single ventricular myocytes. The myocyte was a kind of osmometer since the cell volume was found to be strongly dependent on the perfusion solution osmolarity. This volume change was measured, indirectly, by measuring the cell width change using video-microscopy and image analysis software. Jacob''s equation was used to model these results successfully. Some dual perfusion experiments to see the effects of the localized perfusion of different osmotic solutions to generate an osmotic gradient inside myocytes were also investigated. This device can be useful for studying the effects of localized pH or osmotic gradients inside myocytes, estimating intracellular ion diffusion rates, and inducing regional changes in other important intracellular ions. [Copyright &y& Elsevier]