Showing papers by "David A. Eisner published in 2006"

Reducing Ryanodine Receptor Open Probability as a Means to Abolish Spontaneous Ca2+ Release and Increase Ca2+ Transient Amplitude in Adult Ventricular Myocytes

Abstract: The aim of this work was to investigate whether it is possible to remove arrhythmogenic Ca2+ release from the sarcoplasmic reticulum that occurs in calcium overload without compromising normal systolic release. Exposure of rat ventricular myocytes to isoproterenol (1 micromol/L) resulted in an increased amplitude of the systolic Ca2+ transient and the appearance of waves of diastolic Ca2+ release. Application of tetracaine (25 to 50 micromol/L) decreased the frequency or abolished the diastolic Ca2+ release. This was accompanied by an increase in the amplitude of the systolic Ca2+ transient. Cellular Ca2+ flux balance was investigated by integrating Ca2+ entry (on the L-type Ca2+ current) and efflux (on Na-Ca2+ exchange). Isoproterenol increased Ca2+ influx but failed to increase Ca2+ efflux during systole (because of the abbreviation of the duration of the Ca2+ transient). To match this increased influx the bulk of Ca2+ efflux occurred via Na-Ca2+ exchange during a diastolic Ca2+ wave. Subsequent application of tetracaine increased systolic Ca2+ efflux and abolished the diastolic efflux. The increase of systolic efflux in tetracaine resulted from both increased amplitude and duration of the systolic Ca2+ transient. In the presence of isoproterenol, those Ca2+ transients preceded by diastolic release were smaller than those where no diastolic release had occurred. When tetracaine was added, the amplitude of the Ca2+ transient was similar to those in isoproterenol with no diastolic release and larger than those preceded by diastolic release. We conclude that tetracaine increases the amplitude of the systolic Ca2+ transient by removing the inhibitory effect of diastolic Ca2+ release.

Sodium calcium exchange as a target for antiarrhythmic therapy

Abstract: In search of better antiarrhythmic therapy, targeting the Na/Ca exchanger is an option to be explored. The rationale is that increased activity of the Na/Ca exchanger has been implicated in arrhythmogenesis in a number of conditions. The evidence is strong for triggered arrhythmias related to Ca2+ overload, due to increased Na+ load or during adrenergic stimulation; the Na/Ca exchanger may be important in triggered arrhythmias in heart failure and in atrial fibrillation. There is also evidence for a less direct role of the Na/Ca exchanger in contributing to remodelling processes. In this chapter, we review this evidence and discuss the consequences of inhibition of Na/Ca exchange in the perspective of its physiological role in Ca2+ homeostasis. We summarize the current data on the use of available blockers of Na/Ca exchange and propose a framework for further study and development of such drugs. Very selective agents have great potential as tools for further study of the role the Na/Ca exchanger plays in arrhythmogenesis. For therapy, they may have their specific indications, but they carry the risk of increasing Ca2+ load of the cell. Agents with a broader action that includes Ca2+ channel block may have advantages in other conditions, e.g. with Ca2+ overload. Additional actions such as block of K+ channels, which may be unwanted in e.g. heart failure, may be used to advantage as well.

Life, sudden death, and intracellular calcium.

Abstract: See related articles, pages 283–291 and 292–298 Since the original studies of Ringer,1 calcium (Ca2+) has become almost synonymous with contraction in the heart. Two papers in the current issue of Circulation Research focus on other roles of this cation.1 Wu and Bers2 show that Ca2+ in the nuclear envelope is in a store that is functionally interconnected with the sarcoplasmic reticulum (SR), a result that may have implications for the role of calcium in controlling gene transcription.2 The other area and the main focus of this editorial is the role of Ca2+ ions in arrhythmogenesis. Liu et al3 present important data concerning the occurrence of arrhythmias in a mouse expressing a mutant SR Ca2+ release channel (ryanodine receptor [RyR]). To discuss this result, we will first briefly summarize current concepts in the area. It is now known that most of the calcium that activates contraction comes from an intracellular store (the SR) and is released through the RyR. Release occurs through the process of calcium-induced calcium release. This depends on the fact that the probability of the RyR being open is increased by an increase of cytoplasmic Ca2+ concentration ([Ca2+]i). The entry of a small amount of Ca2+ into the cell through the L-type Ca2+ current thereby triggers much more release from the SR. It has been appreciated for a long time that …