TRIIODOTHYRONINE PREVENTS THE AMIODARONE-INDUCED DECREASE IN THE EXPRESSION OF THE LIVER LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE

Treatment with amiodarone, a potent antiarrhythmic drug, is associated with a dose-dependent increase in plasma cholesterol resulting from a decreased number of liver low-density lipoprotein (LDL) receptors. Si milar changes occur in hypothyroidism, and it has been suggested that amiodarone acts via induction of a local 'hypothyroid-like' state in e xtrathyroidal tissues. The present study was designed to evaluate whet her exogenous tri-iodothyronine (T-3) could prevent the effects of ami odarone on LDL cholesterol. Rats were treated for 14 days with water, amiodarone 10 mg/100 g body weight (BW), or amiodarone and 2.5, 5 or 1 0 mu g T-3/100 g BW respectively. Relative to controls, amiodarone inc reased plasma LDL cholesterol by 31% and decreased liver LDL receptor mRNA by 56% and protein by 45%; liver T-3 content was reduced by 21%. Addition of T-3 to the treatment with amiodarone dose-dependently reve rsed all these changes, with a return to control values of plasma chol esterol and the number of liver LDL receptors, although LDL receptor m RNA remained slightly lower. Treatment of rats for 14 days with T-3 al one (5 mu g/100 g BW) decreased plasma LDL cholesterol by 19% and incr eased liver LDL receptor mRNA by 41%. In conclusion, T-3 prevents the amiodarone-induced changes in plasma LDL cholesterol and liver LDL rec eptor gene expression. These findings suggest that the inhibitory effe ct of amiodarone on LDL receptor gene expression is mediated by T-3-de pendent pathways.