The thyroid hormone analog DITPA restores I(to) in rats after myocardial infarction

Previous studies have established that reductions in repolarizing currents occur in heart disease and can contribute to life-threatening arrhythmias in myocardium. In this study, we investigated whether the thyroid hormone analog 3, 5-diiodothyropropionic acid (DITPA) could restore repolarizing tran...

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Published in:American journal of physiology. Heart and circulatory physiology 2000-04, Vol.278 (4), p.H1105-H1116
Main Authors: Wickenden, A D, Kaprielian, R, You, X M, Backx, P H
Format: Article
Language:English
Subjects:
Action Potentials - drug effects
Animals
Diiodothyronines - pharmacology
Dose-Response Relationship, Drug
Electrophysiology
Gene Expression - drug effects
Heart Ventricles - chemistry
Heart Ventricles - cytology
Heart Ventricles - metabolism
Kv1.4 Potassium Channel
Male
Muscle Fibers, Skeletal - chemistry
Muscle Fibers, Skeletal - metabolism
Myocardial Infarction - drug therapy
Myocardium - chemistry
Myocardium - cytology
Myocardium - metabolism
Potassium - metabolism
Potassium Channels - genetics
Potassium Channels - metabolism
Potassium Channels, Voltage-Gated
Propionates - pharmacology
Rats
Rats, Inbred Lew
Receptors, Thyroid Hormone - physiology
RNA, Messenger - analysis
Shal Potassium Channels
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Summary:Previous studies have established that reductions in repolarizing currents occur in heart disease and can contribute to life-threatening arrhythmias in myocardium. In this study, we investigated whether the thyroid hormone analog 3, 5-diiodothyropropionic acid (DITPA) could restore repolarizing transient outward K(+) current (I(to)) density and gene expression in rat myocardium after myocardial infarction (MI). Our findings show that I(to) density was reduced after MI (14.0 +/- 1.0 vs. 10.2 +/- 0.9 pA/pF, sham vs. post-MI at +40 mV). mRNA levels of Kv4.2 and Kv4.3 genes were decreased but Kv1.4 mRNA levels were increased post-MI. Corresponding changes in Kv4.2 and Kv1.4 protein were also observed. Chronic treatment of post-MI rats with 10 mg/kg DITPA restored I(to) density (to 15.2 +/- 1.1 pA/pF at +40 mV) as well as Kv4.2 and Kv1.4 expression to levels observed in sham-operated controls. Other membrane currents (Na(+), L-type Ca(2+), sustained, and inward rectifier K(+) currents) were unaffected by DITPA treatment. Associated with the changes in I(to) expression, action potential durations (current-clamp recordings in isolated single right ventricular myocytes and monophasic action potential recordings from the right free wall in situ) were prolonged after MI and restored with DITPA treatment. Our results demonstrate that DITPA restores I(to) density in the setting of MI, which may be useful in preventing complications associated with I(to) downregulation.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.2000.278.4.h1105