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 i n myocardium. In this study, we investigated whether the thyroid hormone an alog 3,5-diiodothyropropionic acid (DITPA)! could restore repolarizing tran sient outward K+ current (I-to) density and gene expression in rat myocardi um after myocardial infarction (MI). Our findings show that I-to density wa s reduced after MI (14.0 +/- 1.0 vs. 10.2 +/- 0,9 pA/pF, sham vs. post-MI a t +40 mV). mRNA levels of Kv4.2 and Kv4.3 genes were decreased but Kv1.4 mR NA 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 K L,4.2 and Kv1.4 expression to levels observed in sham-operated controls. Ot her membrane currents (Na+, L-type Ca2+, 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 r estored with DITPA treatment. Our results demonstrate that DITPA restores I -to density in the setting of MI, which may be useful in preventing complic ations associated with I-to downregulation.