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. 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 Ca(2+)-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 ionomycin 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).
Roussel
J P
JP
Département de Biologie-Santé Université de Montpellier, France.
Grazzini
E
E
Guipponi
M
M
Astier
H
H
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D004357:Drug Synergism; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013972:Thyrotropin / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D010446:Peptide Fragments; D011498:Protein Precursors; D014284:Triiodothyronine; C057639:prepro-thyrotropin releasing hormone (160-169); D013973:Thyrotropin-Releasing Hormone; C038806:1,4-dihydropyridine; D013972:Thyrotropin; D009543:Nifedipine; C036116:desethylamiodarone; D000638:Amiodarone; D002118:Calcium