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 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.
Wickenden
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Departments of Physiology and Medicine and The Center for Cardiovascular Research, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
Kaprielian
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Backx
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D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004104:Diiodothyronines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D015870:Gene Expression / Q000187:drug effects; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D051665:Kv1.4 Potassium Channel; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011422:Propionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D051672:Shal Potassium Channels
D004104:Diiodothyronines; C496979:Kcna4 protein, rat; C497020:Kcnd2 protein, rat; C497023:Kcnd3 protein, rat; D051665:Kv1.4 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011422:Propionates; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D051672:Shal Potassium Channels; C082182:3,5-diiodothyropropionic acid; D011188:Potassium