Na-ca Exchange And Ca Fluxes During Contraction And Relaxation In Mammalian Ventricular Muscle

There are four cellular Ca transport systems which compete to remove Ca from the myoplasm in mammalian ventricular myocytes. These are 1) the SR Ca-ATPase, 2) the sarcolemmal Na-Ca exchange, 3) the sarcolemmal Ca-ATPase and 4) the mitochondrial Ca uniporter. Using multiple experimental approaches we have evaluated the dynamic interaction of these systems during the normal cardiac contraction-relaxation cycle. The SR Ca-ATPase and Na-Ca exchange are clearly the most important, quantitatively; however, the relative roles vary in a species-dependent manner. In particular, the SR is much more strongly dominant in rat ventricular myocytes, where ~ 92% of Ca removal is via SR Ca-ATPase and only 7% via Na-Ca exchange during a twitch. In other species (rabbit, ferret, cat, and guinea pig) the balance is more in the range of 70% SR Ca-ATPase and 25-30% Na-Ca exchange. Ferret ventricular myocytes also exhibit an unusually strong sarcolemmal Ca-ATPase. During the steady state the same amount of Ca must leave the cell as enters over a cardiac cycle. This implies that 25-30% of the Ca required to activate contraction must enter the cell, and experiments demonstrate that this amount of Ca may be supplied by the L-type Ca current.779430442Bers, D.M., (1991) Excitation-Contraction Coupling and Cardiac Contractile Force, pp. 1-258. , (Single author monograph.) Kluwer Academic Press. Dordrecht, NetherlandsSutko, J.L., Willerson, J.T., Ryanodine alteration of the contractile state of rat ventricular myocardium. Comparison with dog, cat and rabbit ventricular tissues (1980) Circ. Res., 46, pp. 332-343Bers, D.M., Ca influx and SR Ca release in cardiac muscle activation during postrest recovery (1985) Am. J. Physiol., 248, pp. H366-H381Bers, D.M., Mechanisms contributing to the cardiac inotropic effect of Na-pump inhibition and reduction of extracellular Na (1987) J. Gen. Physiol., 90, pp. 479-504Bers, D.M., Christensen, D.M., Nguyen, T.X., Can Ca entry via Na-Ca exchange directly activate cardiac muscle contraction? (1988) J. Mol. Cell. Cardiol., 20, pp. 405-414Beuckelmann, D.J., Wier, W.G., Mechanism of release of calcium from sarcoplasmic reticulum of guinea pig cardiac cells (1988) J. Physiol., 405, pp. 233-255Fabiato, A., Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell (1985) J. Gen. Physiol., 85, pp. 247-290Leblanc, N., Hume, J.R., Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum (1990) Science, 248, pp. 372-376Levi, A.J., Spitzer, K.W., Kohmoto, O., Bridge, J.H.B., Depolarization-induced Ca entry via Na-Ca exchange triggers SR release in guinea pig cardiac myocytes (1994) Am. J. Physiol., 266, pp. H1422-H1433Kohmoto, O., Levi, A.J., Bridge, J.H.B., Relation between reverse sodium-calcium exchange and sarcoplasmic reticulum calcium release in guinea pig ventricular cells (1994) Circ. Res., 74, pp. 550-554Bassani, R.A., Bassani, J.W.M., Bers, D.M., Mitochondrial and sarcolemmal Ca transport can reduce [Ca]i during caffeine contractures in rabbit cardiac myocytes (1992) J. Physiol., 453, pp. 591-608Bassani, J.W.M., Bassani, R.A., Bers, D.M., Relaxation in rabbit and rat cardiac cells: Species-dependent differences in cellular mechanisms (1994) J. Physiol., 476, pp. 279-293Bassani, R.A., Bassani, J.W.M., Bers, D.M., Relaxation in ferret ventricular myocytes: Unusual interplay among calcium transport systems (1994) J. Physiol., 476, pp. 295-308Bers, D.M., Bridge, J.H.B., Relaxation of rabbit ventricular muscle by Na-Ca exchange and sarcoplasmic reticulum Ca-pump: Ryanodine and voltage sensitivity (1989) Circ. Res., 65, pp. 334-342Bridge, J.H.B., Relationships between the sarcoplasmic reticulum and transarcolemmal Ca transport revealed by rapidly cooling rabbit ventricular muscle (1986) J. Gen. Physiol., 88, pp. 437-473Bers, D.M., Bridge, J.H.B., Spitzer, K.W., Intracellular Ca transients during rapid cooling contractures in guinea-pig ventricular myocytes (1989) J. Physiol., 417, pp. 537-553Bers, D.M., Lederer, W.J., Berlin, J.R., Intracellular Ca transients in rat cardiac myocytes: Role of Na/Ca exchange in excitation-contraction coupling (1990) Am. J. Physiol., 258, pp. C944-C954Hryshko, L.V., Stiffel, V.M., Bers, D.M., Rapid cooling contractures as an index of SR Ca content in rabbit ventricular myocyte (1989) Am. J. Physiol., 257, pp. H1369-H1377Hove-Madsen, L., Bers, D.M., SR Ca uptake and thapsigargin sensitivity in permeabilized rabbit and rat ventricular myocytes (1993) Cir. Res., 73, pp. 820-828Bassani, J.W.M., Bassani, R.A., Bers, D.M., Twitch-dependent SR Ca accumulation and release in rabbit ventricular myocytes (1993) Am. J. Physiol., 265, pp. C533-C540Bassani, R.A., Bers, D.M., Rate of diastolic Ca release from the sarcoplasmic reticulum of intact rabbit and rat ventricular myocytes (1995) Biophys. J., 68, pp. 2015-2022Bassani, J.W.M., Yuan, W., Bers, D.M., Fractional SR Ca release is altered by trigger Ca and SR Ca content in cardiac myocytes (1995) Am. J. Physiol., 268, pp. 1313-1319Gatto, C., Milanick, M.A., Inhibition of the red blood cell calcium pump by eosin and other fluorescein analogues (1993) Am. J. Physiol., 264, pp. C1577-C1586Gatto, C., Hale, C.C., Milanick, M.A., Eosin, a potent inhibitor of the plasma membrane Ca pump, does not inhibit the cardiac Na-Ca exchanger (1995) Biochemistry, 34, pp. 965-972Bassani, R.A., Bassani, J.W.M., Bers, D.M., Relaxation in ferret ventricular myocytes: Role of the sarcolemmal Ca ATPase (1995) Pflüg. Arch., 430, pp. 573-579Hove-Madsen, L., Bers, D.M., Passive Ca buffering and SR Ca uptake in permeabilized rabbit ventricular myocytes (1993) Am. J. Physiol., 264, pp. C677-C686Negretti, N., O'Neill, S.C., Eisner, D.A., The relative contributions of different intracellular and sarcolemmal systems to relaxation in rat ventricular myocytes (1993) Cardiovasc. Res., 27, pp. 1826-1830Crespo, L.M., Grantham, C.J., Cannell, M.B., Kinetics, stoichiometry and role of the Na-Ca exchange mechanism in isolated cardiac myocytes (1990) Nature, 345, pp. 618-621Puglisi, J.L., Bassani, R.A., Bassani, J.W.M., Amin, J.N., Bers, D.M., Temperature and the relative contributions of Ca transport systems in cardiac myocyte relaxation (1996) Am. J. Physiol., , In pressDelbridge, L.M., Bassani, J.W.M., Bers, D.M., Steady-state twitch Ca fluxes and cytosolic Ca buffering in rabbit ventricular myocytes (1996) Am. J. 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Compound Mutations in Long QT Syndrome Assessed by a Computer Model

Long QT syndrome (LQTS) is an electrical disorder that predisposes affected individuals to sudden death from cardiac arrhythmias. Recently, it has been shown that compound mutations in LQTS are more common than expected and cause a severe phenotype. We used a mathematical model of rabbit ventricular myocyte (LabHEART) to investigate the simultaneous effects of three compound mutations reported in LQTS patients. Our results show that the mutations prolong the action potential (AP), being the impact of compound mutations stronger than the additive effects of single ones. The user-friendly characteristic of LabHEART allows combining easily different levels of current alterations to evaluate their outcome. This feature makes it an invaluable tool for researchers who want to explore the effects of channel mutations on the AP waveform

Computer Simulation of Altered Sodium Channel Gating in Rabbit and HumanVentricular Myocytes

Mathematical models were used to explore sodium (Na) current alterations. Markovian representations were chosen to describe the Na current behavior under pathological conditions, such as genetic defects (Long QT and Brugada syndromes) or acquired diseases (heart failure). These Na current formulations were subsequently introduced in an integrated model of the ventricular myocyte to investigate their effects on the ventricular action potential. This "in silico" approach is a powerful tool, providing new insights into arrhythmia susceptibility due to inherited and/or acquired Na channelopathies