Examination of the Changes in Calcium Homeostasis in the Delayed Antiarrhythmic Effect of Sodium Nitrite.

Vivien Demeter-Haludka,János Prorok,Ágnes Végh,Norbert Nagy,Mária Kovács,András Varró

doi:10.3390/ijms20225687

Vivien Demeter-Haludka, János Prorok + Show 4 more

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https://doi.org/10.3390/ijms20225687

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Abstract

We have evidence that the intravenous infusion of sodium nitrite (NaNO2) results in an antiarrhythmic effect when given 24 h prior to an ischemia and reperfusion (I/R) insult in anaesthetized dogs. This protection was associated with the reduction of reactive oxygen species resulting from I/R through the attenuation of mitochondrial respiration. Here, we examined whether the changes in calcium, which also contributes to arrhythmia generation, play a role in the NaNO2-induced effect. On the first day, 30 anaesthetized dogs were treated either with saline or NaNO2 (0.2 µmol/kg/min) for 20 min. Some animals were subjected to a 25 min LAD (anterior descending branch of the left coronary artery) occlusion and 2 min reperfusion (I/R = 4; NaNO2-I/R = 6), or the heart was removed 24 h later. We have shown that nitrite prevented the I/R-induced increase in cellular and mitochondrial calcium deposits. During simulated I/R, the amplitude of the calcium transient and the diastolic calcium level were significantly lower in the nitrite-treated hearts and the ERP (effective refractory period) fraction of the action potential was significantly increased. Furthermore, nitrite also enhanced the mitochondrial respiratory response and prevented the MPTPT opening during calcium overload. These results suggest that nitrite can reduce the harmful consequences of calcium overload, perhaps directly by modulating ion channels or indirectly by reducing the mitochondrial ROS (reactive oxygen species) production.

Highlights

Severe ventricular arrhythmias resulting from an acute ischemia and reperfusion (I/R) insult are the main cause of sudden cardiac death
Compared to the sham-operated controls, in samples taken from dogs subjected to a 25 min period of I/R, the number of calcium deposits within the cell and in the mitochondria was significantly increased in all examined regions
This study aimed to examine whether changes in calcium homeostasis play a role in the delayed antiarrhythmic effect of sodium nitrite

Summary

Introduction

Severe ventricular arrhythmias resulting from an acute ischemia and reperfusion (I/R) insult are the main cause of sudden cardiac death. We have previous evidence that inorganic nitrite administered immediately prior to a 25 min coronary artery occlusion, or during the occlusion period but prior to reperfusion, markedly attenuated these ischemia-induced arrhythmias and increased survival in anaesthetized dogs. We have evidence that sodium nitrite administered 24 h before the coronary artery occlusion and reperfusion provides a significant protection against the arrhythmias [2]. This marked delayed antiarrhythmic effect of nitrite has been found to be associated with an attenuation of mitochondrial reactive oxygen species (ROS) formation resulting from the depressed mitochondrial respiration by nitrite [3]

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