DIHYDROPYRIDINE-LIKE EFFECTS OF AMIODARONE AND DESETHYLAMIODARONE ON THYROTROPIN SECRETION AND INTRACELLULAR CALCIUM-CONCENTRATION IN RAT PITUITARY

Amiodarone (AM) and its major metabolite desethylamiodarone (DEA) are structurally similar to biologically active thyroid hormones. Amiodaro ne therapy is frequently associated with impairment of thyrotropic fun ction, whose mechanisms are still controversial. Besides its effect on nuclear thyroid hormone binding, AM is able to displace dihydropyridi ne (DH) binding on membrane preparations from several tissues. By peri fusing rat pituitary fragments and measuring thyrotropin (TSH) release we examined: the effect of AM on Ca2+-dependent and DHP-sensitive pot entiation of the TSH response to thyrotropin-releasing hormone (TRH) i nduced by either triiodothyronine (T-3, perifused for only 30 min befo re a TRH pulse) or by the prepro-TRH peptide 160-169 (PS4); and the ef fect of DEA on TRH-induced TSH response in the presence or absence of the DHP nifedipine. We show that AM reverses T-3 or PS4 potentiation o f the TSH response to TRH; this effect is specific because AM does not modify ionomycin potentiation of that response. In contrast, DEA sign ificantly potentiates the TSH response to TRH and the DHP nifedipine r everses that potentiation. We also tested whether AM would change the acute T-3-induced increase in intracellular Ca2+ concentration by meas uring intracellular Ca2+ ([Ca2+])(i) with fura 2 imaging on primary cu ltures of pituitary cells. We show that AM reverses the effect of T-3 on [Ca2+](i) as well as the PS4-induced increase in [Ca2+](i). In cont rast, DEA increases [Ca2+](i) and nifedipine reverses this effect. Our results suggest that AM and DEA display DHP-like effects on TRH-induc ed TSH release, behaving either as a Ca2+ channel blocker (AM) or as a Ca2+ channel agonist (DEA).