Rat Models of Ventricular Fibrillation Following Acute Myocardial Infarction

A number of animal models have been designed in order to unravel the underlying mechanisms of acute ischemia-induced arrhythmias and to test compounds and interventions for antiarrhythmic therapy. This is important as acute myocardial infarction (AMI) continues to be the major cause of sudden cardiac death, and we are yet to discover safe and effective treatments of the lethal arrhythmias occurring in the acute setting. Animal models therefore continue to be relevant for our understanding and treatment of acute ischemic arrhythmias. This review discusses the applicability of the rat as a model for ventricular arrhythmias occurring during the acute phase of AMI. It provides a description of models developed, advantages and disadvantages of rats, as well as an overview of the most important interventions investigated and the relevance for human pathophysiology.

Soluble epoxide hydrolase inhibitors might prevent ischemic arrhythmias via microRNA-1 repression in primary neonatal mouse ventricular myocytes

Ischemic arrhythmias are the main causes of sudden cardiac death.

MiR-223-3p as a Novel MicroRNA Regulator of Expression of Voltage-Gated K+ Channel Kv4.2 in Acute Myocardial Infarction

Background/Aims: Acute myocardial infarction (AMI) is a devastating cardiovascular disease with a high rate of morbidity and mortality, partly due to enhanced arrhythmogenicity. MicroRNAs (miRNAs) have been shown to participate in the regulation of cardiac ion channels and the associated arrhythmias. The purpose of this study was to test our hypothesis that miR-223-3p contributes to the electrical disorders in AMI via modulating KCND2, the gene encoding voltage-gated channel Kv4.2 that carries transient outward K+ current Ito. Methods: AMI model was established in male Sprague-Dawley (SD) rats by left anterior descending artery (LAD) ligation. Evans blue and TTC staining was used to measure infarct area. Ito was recorded in isolated ventricular cardiomyocytes or cultured neonatal rat ventricular cells (NRVCs) by whole-cell patch-clamp techniques. Western blot analysis was employed to detect the protein level of Kv4.2 and real-time RT-PCR to determine the transcript level of miR-223-3p. Luciferase assay was used to examine the interaction between miR-223-3p and KCND2 in cultured NRVCs. Results: Expression of miR-223-3p was remarkably upregulated in AMI relative to sham control rats. On the contrary, the protein level of Kv4.2 and Ito density were significantly decreased in AMI. Consistently, transfection of miR-223-3p mimic markedly reduced Kv4.2 protein level and Ito current in cultured NRVCs. Co-transfection of AMO-223-3p (an antisense inhibitor of miR-223-3p) reversed the repressive effect of miR-223-3p. Luciferase assay showed that miR-223-3p, but not the negative control, substantially suppressed the luciferase activity, confirming the direct binding of miR-223-3p to the seed site within the KCND2 sequence. Finally, direct intramuscular injection of AMO-223-3p into the ischemic myocardium to knockdown endogenous miR-223-3p decreased the propensity of ischemic arrhythmias. Conclusions: Upregulation of miR-223-3p in AMI repressed the expression of KCND2/Kv4.2 resulting in reduction of Ito density that can cause APD prolongation and promote arrhythmias in AMI, and therefore knockdown of endogenous miR-223-3p might be considered a new approach for antiarrhythmic therapy of ischemic arrhythmias.

A Comparative Study of Toxicity and the Scale of Activity of New N-Substituted Benzamide Derivative

A promising search direction of modern scientists, involved in antiarrhythmic researchs, is the creation of substances that can suppress the repolarization phase of the action potential of myocardial cells. At the same time, the well-known domestic representative of this group of substances – the Nibentan – has a number of undesirable effects. To correct for these effects, the chemical compound the Nibentan with L-glutamic acid as the anion was created. In experi-ments on mice, it was found that the acute toxicity of the compound is N-substituted Benzamide derivative – Racemate Nibentan with L-glutamic acid is below 1.6 times at the intra-peritoneal injection in comparison with the acute toxicity structural analogue the Nibentan. Studied chemical compound in the range of doses from 1 to 5 % from DL50 suppresses reproduction acontinued disturbances of cardiac rhythm, which may serve as evidence of the ability of compounds to inhibit sodium ion currents through the membrane of cardiomyocytes. The compound of the Racemate Nibentan with L-glutamic acid also has a great therapeutic effect on aconitine arrhythmiac model in rats. On the model of transient ischemic arrhythmias a new compound Nibentan with comparable anti-arrhythmic activity in doses of 5 and 2.5 % from LD50, exceeds the reference product to prevent the formation of occlusion and reperfusion ventricular fibrillation in acute experience on cats. This work was supported by the project (project code - 2859) performed in Mordovia State N.P. Ogarev University under Government job and grant RFBR 14-04-31104.