Showing papers by "David A. Eisner published in 2003"

Sarcoplasmic Reticulum Ca2+ and Heart Failure: Roles of Diastolic Leak and Ca2+ Transport

Abstract: Heart failure (HF) is a leading cause of death and enormous effort has focused at understanding the molecular and cellular mechanisms of the decreased cardiac contractility. While changes of other components contribute, it is generally agreed that much of the contractile deficit is due to reduced myocyte Ca2+ transients.1,2 Alterations in Ca2+ current ( I Ca) and action potential characteristics are also seen in HF, but a central factor limiting Ca2+ transient amplitude is a decrease of sarcoplasmic reticulum (SR) Ca2+ content.3–6 HF is extremely complex, but it is easy to appreciate how reduced SR Ca2+ content would reduce SR Ca2+ release, myofilament activation, and contractility. Despite agreement that SR Ca2+ content is reduced in HF, controversy exists about why SR content is low. SR Ca2+ content reflects the balance between Ca2+ uptake (via SERCA) and Ca2+ efflux via ryanodine receptor (RyR). Thus, reduced SR content in HF must be due to reduced Ca2+ pumping by SERCA or increased SR Ca2+ leak via RyRs. Both are supported by experimental data (below). Transsarcolemmal Ca2+ fluxes also affect SR Ca2+ load. That is, reduced Ca2+ influx (eg, via I Ca) or enhanced Ca2+ extrusion via Na+-Ca2+ exchange (NCX) can unload the SR. Results are not unanimous, but most groups find little alteration in peak I Ca density in HF, while many find evidence of enhanced NCX expression and function.1,2 Increased NCX function can compete with SERCA during [Ca2+]i decline, extruding more Ca2+ from the cell and depleting the SR. In the new steady state, a larger fraction of activating Ca2+ also enters the cell at each beat in HF (eg, smaller Ca2+ release causes less …

Normal and pathological excitation-contraction coupling in the heart -- an overview.

Abstract: This issue of The Journal of Physiology includes a series of review articles arising from a symposium held at the joint meeting of the UK, German and Scandinavian Physiological Societies. The articles focus on different aspects of the cellular control of contraction. The basic mechanism of cardiac excitation-contraction coupling (‘calcium-induced calcium release’) is now reasonably well-established. Calcium enters the cell from the extracellular fluid via the voltage-dependent L-type Ca2+ channel. This results in a ‘trigger’ increase of [Ca2+]i in the space between the sarcolemma and sarcoplasmic reticulum (SR) and this leads to the opening of the SR Ca2+ release channel or ‘ryanodine receptor’ (RyR). As exemplified by the papers from the symposium, much current work is focused on how this mechanism is modified in different circumstances. These include autonomic modulation, but also pathological conditions such as cardiac hypertrophy and failure, a recurrent theme in several of these papers. Cardiac action potentials have a variety of different shapes. The classical long plateau, essential for preventing re-excitation and arrhythmias, can often be preceded by an initial rapid repolarization that results from the transient outward (potassium) current. The amplitude of this current (and therefore the prominence of the rapid repolarization) varies between regions of the ventricle and in heart failure. Cellular cardiac physiologists often belong to two communities: electrophysiologists who are concerned with such byzantine complexities of action potential shape and those interested in excitation-contraction coupling who tend to be less focused on these issues. Peter Backx and coworkers show that an integrated approach is needed as a change in the initial rate of repolarization can have pronounced effects on the Ca2+ transient. Decreasing the rate of repolarization can decrease the Ca2+ transient, probably because at positive voltages the current through single L-type channels is less than that at negative voltages. Furthermore, the slowed repolarization results in desynchronized Ca2+ release analogous to that seen in failure. Since heart failure is often accompanied by a decrease in the transient outward potassium current, these studies provide an interesting perspective to what at first glance seems to concern electrophysiologists only. The vast majority of papers on cardiac excitation- contraction coupling deal with the ventricle. The paper by Lothar Blatter et al. restores attention to the atrium. The less prominent transverse tubular system in the atrium (compared to the ventricle) means that the sarcolemmal Ca2+ channels can only trigger Ca2+ release from SR located near the periphery of the cell. This results in Ca2+ release from the periphery of the cell that then spreads as a wave into the interior triggering Ca2+ release from more centrally located SR. This observation is of interest for at least two reasons. (1) It shows that Ca2+ waves, which are often thought to be pathological in the ventricle, underpin normal excitation- contraction coupling in the atrium. (2) The paper also shows that the resulting Ca2+ release can alternate in amplitude from beat to beat. ‘Alternans’ is well known to occur in diseased conditions and this work shows a cellular basis for it. Since the newest working hypotheses on the mechanisms of atrial fibrillation are focusing on abnormal automaticity, it will be of interest to examine these particular mechanisms in diseased atrial myocytes, a currently unexplored field. Perhaps the greatest current challenge to cellular cardiac physiologists is to explain why the heart beats more weakly in failure. At a cellular level there are many hypotheses of which the SR is central to most. However, as summarized by Ole Sejersted and coworkers, it is still controversial as to exactly what the SR defect is. Altered Ca2+ release and decreased SR content have both been suggested and, in the latter case, it is uncertain as to whether the change of content results from decreased pumping of Ca2+ into the SR or increased leak out. This paper contains another important message that, where possible, heart failure should be investigated using a variety of techniques from the whole heart to the subcellular level. In particular, one must be aware of the potential problems caused by cell dialysis. Cellular changes may indeed be quite diverse in different stages of cardiac remodelling. Information on the in vivo cardiac and haemodynamic status is essential for classification and correct interpretation of the cellular observations. eNOS and NO production are more immediately associated with the regulation of vascular tone than with regulation of cardiac function. Yet eNOS appears to be prominently expressed in ventricular myocytes as well and is part of the autonomic regulation of heart rate and contraction, as reviewed by Massion & Balligand. Many of these insights have been gained from the use of transgenic mice, lacking eNOS. Different groups have studied the role of eNOS and NO in the signalling cascade of muscarinic receptor stimulation with different results. The authors join the point of view that this mechanism may be redundant for the muscarinic pathway. eNOS and NO are also part of the signalling cascade for the β3 adrenergic receptor, contributing to a negative inotropic effect. In heart failure with an altered balance between β3 and the cAMP-linked β1/β2 receptors, eNOS may thus contribute to a weaker contraction. On the other hand, eNOS by itself may be cardioprotective, as eNOS−/- mice are more prone to remodelling after myocardial infarction. These latter results offer interesting perspectives for modulation of NO production in heart failure. A very different approach to improve cardiac function in heart failure is presented by del Monte & Hajjar. These authors were the first to explore the potential of gene transfer to raise the levels of SERCA, the sarco- and endoplasmic reticulum Ca2+-ATPase, in ventricular myocytes of failing hearts. In many studies it has been shown that expression and function of this protein is reduced in heart failure. Gene transfer of SERCA in myocytes from failing heart indeed restores contractile function. Using transgenic techniques decreasing the phospholamban inhibition of SERCA function equally enhances cardiac systolic and diastolic function. Is this just a sophisticated proof of principle, or a realistic approach to treat heart failure? The authors review the current available technology and express cautious optimism. Even if gene therapy should not live up to these expectations, it will most certainly have contributed substantially to our insights in physiology and pathophysiology of cardiac excitation-contraction coupling. This collection of reviews illustrates how studies of excitation- contraction coupling are being integrated into a wider perspective on cardiac function, with particular emphasis on the changes in heart failure. We trust they will stimulate further work in the field.

Illuminating sarcoplasmic reticulum calcium.

Abstract: The bulk of the Ca2+ that activates contraction in the heart comes from the sarcoplasmic reticulum (SR). Calcium is released by the process of Ca2+-induced Ca2+ release (CICR) in which the entry of a small amount of Ca2+ across the cell membrane triggers the release of much more from the SR. This mechanism depends on the fact that Ca2+ entry from the extracellular fluid (via the L-type Ca2+ current) increases the probability that the SR Ca2+ release channel (ryanodine receptor, RyR) is open. The greater the open probability of the RyR, the greater the release of Ca2+ from the SR and therefore the larger the contraction of the heart. A major factor determining the contractility of the heart is the Ca2+ content of the SR. As one might expect, the more Ca2+ that there is in the SR, the more is released on each contraction. However the degree of filling of the SR has other important implications for cardiac physiology and pathology. Excessive filling of the SR (Ca2+ overload) results in Ca2+ release even in the absence of a trigger. When this Ca2+ release occurs in diastole, it can activate inward membrane currents and produce afterdepolarizations. In the field of heart failure, the decrease of the systolic Ca2+ transient is generally associated with a decrease of SR Ca2+ content, although the precise mechanisms responsible for this remain controversial.1,2 Given the importance of SR Ca2+ content, it is essential to be able to measure it. Many previous studies have used indirect methods. A convenient way is to release the SR Ca2+ into the cytoplasm (either by applying caffeine or rapid cooling3,4) and then measure the amplitude of the resulting contraction or …

pH-dependent and -independent effects inhibit Ca2+-induced Ca2+ release during metabolic blockade in rat ventricular myocytes

Abstract: We have investigated the role of changes of intracellular pH (pHi) in the effects of metabolic blockade (cyanide plus 2-deoxyglucose) on Ca2+ release from the sarcoplasmic reticulum (SR) in rat ventricular myocytes. pHi and cell length were measured simultaneously. Metabolic blockade decreased the frequency of Ca2+ waves, an effect previously shown to be due to inhibition of Ca2+ release from the SR. This was accompanied by an intracellular acidification. Intracellular acidification was produced in the absence of metabolic inhibition by application of sodium butyrate. A maintained intracellular acidosis produced a decrease of wave frequency. A hysteresis between pHi and wave frequency was observed such that during the onset of the acidification the wave frequency decreased more than in the steady state. Comparison of the steady state relationship between pHi and wave frequency showed that the decrease of wave frequency produced by metabolic blockade was greater than could be accounted for simply by the accompanying decrease of pHi. In other experiments the buffering power of the solution was increased. Under these conditions, metabolic blockade produced no change of pHi but the decrease of wave frequency persisted. We conclude that, although intracellular acidification occurs during metabolic blockade, it is not responsible for most of the inhibition of Ca2+ release from the SR.