lithium-chloride and Arrhythmias--Cardiac

Glycogen synthase kinase-3 (GSK-3) signaling has been shown to play a role in the regulation of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of antioxidant genes, including heme oxygenase-1 (HO-1). We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction, a status of high reactive oxygen species (ROS), by attenuating nerve growth factor (NGF) expression and whether Nrf2/HO-1 signaling is involved in the protection. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats were treated for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress, as measured by myocardial superoxide, nitrotyrosine, and dihydroethidium fluorescent staining. In concert, myocardial norepinephrine levels and immunohistochemical analysis of sympathetic nerve revealed a significant increase in innervation in vehicle-treated rats compared with sham-operated rats. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those in sham. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administration of LiCl. LiCl stimulated the nuclear translocation of Nrf2 and the transactivation of the Nrf2 target gene HO-1. Inhibition of phosphoinositide 3-kinase by wortmannin reduced the increase in Nrf2 nucleus translocation and HO-1 expression compared with lithium alone. In addition, the lithium-attenuated NGF levels were reversed in the presence of the Nrf2 inhibitor trigonelline, HO-1 inhibitor SnPP, and peroxynitrite generator SIN-1, indicating the role of Nrf2/HO-1/ROS. In conclusion, lithium protects against ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via antioxidant activation of the Nrf2/HO-1 axis.

Topics: Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Evaluation, Preclinical; Heart; Heme Oxygenase-1; Lithium Chloride; Male; Myocardial Infarction; Nerve Growth Factor; NF-E2-Related Factor 2; Protein Transport; Rats, Wistar; Signal Transduction; Sympathetic Nervous System

Status epilepticus (SE) is a seizure or series of seizures that persist for >30 min and often results in mortality. Death rarely occurs during or immediately following seizure activity, but usually within 30 days. Although ventricular arrhythmias have been implicated in SE-related mortality, the effects of this prolonged seizure activity on the cardiac function and susceptibility to arrhythmias have not been directly investigated. We evaluated myocardial damage, alterations in cardiac electrical activity, and susceptibility to experimentally induced arrhythmias produced by SE in rats. SE resulted in seizure-related increases in blood pressure, heart rate, and the first derivative of pressure, as well as modest, diffuse myocyte damage assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. Ten to twelve days following seizures, electrocardiographic recordings showed arrhythmogenic alterations in cardiac electrical activity, denoted by prolonged QT interval corrected for heart rate and QT dispersion. Finally, SE increased susceptibility to experimentally induced (intravenous aconitine) cardiac arrhythmias. These data suggest that SE produces tachycardic ischemia following the activation of the sympathetic nervous system, resulting in cardiac myofilament damage, arrhythmogenic alterations in cardiac electrical activity, and increased susceptibility to ventricular arrhythmias.

Topics: Aconitine; Actin Cytoskeleton; Action Potentials; Animals; Arrhythmias, Cardiac; Biomarkers; Blood Pressure; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Heart Rate; In Situ Nick-End Labeling; Lithium Chloride; Male; Myocardium; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus; Sympathetic Nervous System; Time Factors; Troponin I

Reperfusion of globally ischemic rat hearts causes rapid generation of inositol(1,4,5) trisphosphate [Ins(1,4,5)P(3)] and the development of arrhythmias, following stimulation of alpha(1)-adrenergic receptors by norepinephrine released from the cardiac sympathetic nerves. The heightened inositol phosphate response in reperfusion depends on the activation of the Na(+)/H(+) exchanger, which might reflect a central role for increased Ca(2+)following reverse mode activation of the Na(+)/Ca(2+) exchanger (NCX). Isolated, perfused rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and the content of Ins(1,4,5)P(3) measured by mass analysis or by anion-exchange high performance liquid chromatography (HPLC) following [(3)H]inositol labeling. Reperfusion caused generation of Ins(1,4,5)P(3) (1266+/-401 to 3387+/-256 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01) and the development of arrhythmias. Inhibition of NCX either by reperfusion at low Ca(2+) (1133+/-173 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) or by adding 10 microm KB-R7943, an inhibitor of reverse mode Na(+)/Ca(2+) exchange, prevented the Ins(1,4,5)P(3) response (1151+/-243 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) and the development of ventricular fibrillation. Lower concentrations of KB-R7943 were less effective. Reverse mode activation of NCX is therefore required for the enhanced Ins(1,4,5)P(3) response in early reperfusion, and inhibitors of this transporter may be useful in the prevention of arrhythmias under such conditions.

Topics: Animals; Arrhythmias, Cardiac; Calcium; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Heart; Inositol 1,4,5-Trisphosphate; Lithium Chloride; Male; Models, Biological; Myocardium; Norepinephrine; Perfusion; Rats; Rats, Sprague-Dawley; Reperfusion; Sodium-Calcium Exchanger; Thiourea

It was shown in experiments on conscious rats that intravenous injection of strophanthine in toxic doses provokes heart arrhythmias and death of the animals. Lithium drugs (lithium chloride and lithium hydroxybutyrate) injected during arrhythmias led to a short-lived effect of heart rhythm normalization. Lithium hydroxybutyrate was more effective if administered shortly after strophanthine injection, reducing the latter's cardiotoxic effect and preventing the death of the majority of the animals.

Topics: Animals; Arrhythmias, Cardiac; Chlorides; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Electrocardiography; Hydroxybutyrates; Lithium; Lithium Chloride; Male; Organometallic Compounds; Rats; Solutions; Strophanthins; Time Factors; Wakefulness

In experiments on cats with dissected vagus and aortal nerves under chloralose-urethane anesthesia, ventricular disorders of the cardiac rhythm were induced by ligation of the common carotid arteries. Appearance of arrhythmias was preceded by an increase in the sympathetic activity (recorded from the inferior cardiac or renal nerve) accompanied by a rise of the arterial blood pressure and of the heart rate. Intravenous injection of lithium chloride or hydroxybutyrate resulted in lowering of the sympathetic activity, arterial blood pressure, and heart rate, and led to the recovery of the sinus rhythm.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Complexes, Premature; Carotid Artery Diseases; Cats; Chlorides; Heart Rate; Hydroxybutyrates; Lithium; Lithium Chloride; Organometallic Compounds; Sympathetic Nervous System; Tachycardia

Experiments on rats have shown that intravenous injection of adrenaline in a dose of 0.3-0.4 mg/kg causes cardiac arrhythmia. In this case the primary arrhythmia developing immediately after adrenaline injection is followed by the recovery of sinusal rhythm which was replaced by the secondary arrhythmia. Apart from arrhythmias, there developed pulmonary edema. The animals died 2--3 minutes after adrenaline injections. Lithium chloride and lithium hydroxybutyrate removed the secondary arrhythmia and pulmonary edema. Lithium hydroxybutyrate has proved to be more effective.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chlorides; Epinephrine; Hydroxybutyrates; Lithium; Lithium Chloride; Male; Organometallic Compounds; Pulmonary Edema; Rats