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Dihydropyridine-like effects of amiodarone and desethylamiodarone on thyrotropin secretion and intracellular calcium concentration in rat pituitary

Roussel J-P, Grazzini E, Guipponi M, Astier H. Dihydropyridine-like effects of amiodarone and desethylamiodarone on thyrotropin secretion and intracellular calcium concentration in rat pituitary. Eur J Endocrinol 1995;133:489–98. ISSN 0804–4643

Amiodarone (AM) and its major metabolite desethylamiodarone (DEA) are structurally similar to biologically active thyroid hormones. Amiodarone therapy is frequently associated with impairment of thyrotropic function, whose mechanisms are still controversial. Besides its effect on nuclear thyroid hormone binding, AM is able to displace dihydropyridine (DH) binding on membrane preparations from several tissues. By perifusing rat pituitary fragments and measuring thyrotropin (TSH) release we examined: the effect of AM on Ca²⁺-dependent and DHP-sensitive potentiation of the TSH response to thyrotropin-releasing hormone (TRH) induced by either triiodothyronine (T₃, perifused for only 30 min before a TRH pulse) or by the prepro-TRH peptide 160–169 (PS₄): and the effect of DEA on trh-induced TSH response in the presence or absence of the DHP nifedipine. We show that AM reverses T₃ or PS₄ potentiation of the TSH response to TRH; this effect is specific because AM does not modify does potentiation of that response. In contrast, DEA significantly potentiates the TSH response to TRH and the DHP nifedipine reverses that potentiation. We also tested whether Am would change the acute T₃-induced increase in intracellular Ca²⁺ concentration by measuring intracellular Ca²⁺ ([Ca²⁺])_i with fura-2 imaging on primary cultures of pituitary cells. We show that AM reverses the effect of T₃ on [Ca²⁺]_i as well as the PS₄-induced increase in [Ca²⁺]_i. In contrast, DEA increases [Ca²⁺]_i and nifedipine reverses this effect. Our results suggest that AM and DEA display DHP-like effects on TRH-induced TSH release, behaving either as a Ca²⁺ channel blocker (AM) or as a Ca²⁺ channel agonist (DEA).

H Astier, Laboratoire de Neurobiologie Endocrinologique, URA 1197 CNRS, Departement de Biologie-Santé Université de Montpellier 2, Place E. Bataillon, 34095 Montpellier Cedex 05, France