title: Autonomic and cellular mechanisms mediating detrimental cardiac effects of status epilepticus.
abstract: Prolonged seizure activity (status epilepticus; SE) can result in increased susceptibility to lethal ventricular arrhythmias for an extended period of time following seizure termination. SE is accompanied by acute, intense activation of the sympathetic nervous system (SymNS) and results in myocyte myofilament damage, arrhythmogenic alterations in cardiac electrical activity, and increased susceptibility to ventricular arrhythmias. However, the mechanisms mediating the changes in cardiac function, and the specific arrhythmogenic substrate produced during SE are unknown. To determine if detrimental cardiac effects of SE are mediated by SymNS stimulation of the heart, we examined the effects of B-adrenergic blockade (atenolol) during seizure activity on blood pressure, heart rate, myocyte myofilament injury (cardiac troponin I, cTnI), electrocardiographic activity, and susceptibility to arrhythmias. Furthermore, we determined if SE was associated with altered expression of the Kv4.x potassium channels, which are critical for action potential repolarization and thereby contribute significantly to normal cardiac electrical activity. Lithium-pilocarpine induced SE was associated with acute tachycardia, hypertension, and cardiomyocyte damage. Arrhythmogenic alterations in cardiac electrical activity accompanied by increased susceptibility to experimentally induced arrhythmias were evident during the first 2 weeks following SE. Both were prevented by atenolol treatment during seizures. Furthermore, one and two weeks after SE, myocyte ion channel remodeling, characterized by a decreased expression of cardiac Kv4.2 potassium channels, was evident. These data suggest that the cardiac effects of prolonged and intense SymNS activation during SE induce myofilament damage and downregulation of Kv4.2 channels, which alter cardiac electrical activity and increase susceptibility to lethal arrhythmias.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84121, United States. steven.bealer@utah.edu
authors.forename: Steven L
authors.initials: SL
authors.lastname: Bealer
authors.forename: Jason G
authors.initials: JG
authors.lastname: Little
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Metcalf
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brewster
authors.forename: Anne E
authors.initials: AE
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D001794:Blood Pressure / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology*; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000502:physiology; D013226:Status Epilepticus / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D019210:Troponin I / Q000097:blood
chemical_list: D051672:Shal Potassium Channels; D019210:Troponin I