Abstract
Abstract Objective The sodium/calcium exchanger (NCX) and the L-type Ca2+-channel (LTCC) are nowadays considered the major transmembrane transport mechanisms that control Ca2+ homeostasis. In pathophysiological conditions the altered function of these currents may influence the Ca2+ homeostasis and cardiac contractility and thereby, may enhance the development of severe tachyarrhythmias. The blockade of NCX current has been proposed as possible approach in the prevention and/or suppression of arrhythmias; however, this mechanism is not always favourable because the inhibition of both modes of NCX may induce Ca2+-overload. The decrease of the Ca2+ level by partial LTCC inhibition may be beneficial in increasing the antiarrhythmic efficacy. Therefore, the aim of our study was to investigate the antiarrhythmic effects of combined NCX and LTCC blockade in the ex vivo guinea pig arrhythmia model. Methods We have performed Langendorff experiments in isolated guinea pig hearts. We have recorded electrocardiograms (ECG) and left ventricle pressure. We have applied 1 μM ORM-10962 (ORM), a compound that block NCX current and 30 nM nisoldipine for the inhibition of LTCC. Arrhythmias have been provoked by decreasing the activity of the sodium/potassium pump with 5 μM ouabain. Results We found that neither LTCC nor NCX blockade alone increased, while the combined inhibition of the two currents significantly delayed (p<0.05) the mean time of appearance of ouabain-induced ventricular fibrillation. The heart frequency was affected by none of the drugs, only the left ventricular pressure (end-systolic and diastolic difference) was significantly elevated by ORM (p<0.001). Conclusion In the Langendorff-perfused guinea pig heart, specific, combined NCX and LTCC blockade may be favourable than the inhibition of NCX or LTCC alone. However, further investigations are necessary to identify the pathological settings in which this combined cardiac drug therapy may be a potential new approach.
Highlights
The cardiovascular diseases are life threatening pathological conditions, which are best illustrated by EU statistics indicating that the ischaemic heart diseases were the main cause of death in Europe[13,14]
Averaging the time to onset of ventricular fibrillation, we found that neither L-type Ca2+-channel (LTCC) inhibition nor NCX inhibition had a significant protective effect on hearts, whereas combined inhibition significantly delayed the onset of ventricular fibrillation compared to control (p
Main findings The main finding of this study was: i) the sodium-calcium exchanger (NCX) blocker ORM-10162 -according with literature data- during preincubation period significantly increased the left ventricular pressure, while the L-type calcium channel (LTCC) inhibitor nisoldipine neither alone nor in combination with ORM compound altered substantially the cardiac pump function; ii) ORM and Niso monotherapy did not prevent the ouabain induced cardiac arrhythmias, ie, did not delayed the time of appearance of ventricular tachycardia (VT)/ventricular fibrillation (VF), while the combination of the drugs significantly delayed it, ie. the combined NCX+LTCC blockade possess antiarrhythmic potency against triggered arrhythmias
Summary
The cardiovascular diseases are life threatening pathological conditions, which are best illustrated by EU statistics indicating that the ischaemic heart diseases were the main cause of death in Europe[13,14]. The reverse mode of the NCX is activated when the cytoplasmic Na+ level is increased and the Ca2+ concentration is low and/or the membrane potential is depolarized In this mode the NCX extrudes three Na+ from the cell and moving one Ca2+ into the cell, and it can generate repolarizing net current. NCX operates mainly in forward mode and removes the same amount of Ca2+ that entered the cell through ICaL maintaining the beat-to-beat Ca2+ balance. In the excitationcontraction coupling (ECC), Ca2+ ions enter the cell from the extracellular space (Ca2+-influx) mainly via inward L-type calcium current (ICaL, LTCC). These channels are primarily present at sarcolemmal-sarcoplasmatic reticulum (SR) junctions, in the vicinity of ryanodine receptors (RyRs). In steady state, during each cycle, the released and reuptake Ca2+, as well as the entered and extruded Ca2+ must be equal
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