Effect of Trifluoperazine, D600, and Phenytoin on Depolarization- and Thyrotropin-Releasing Hormone- Induced Thyrotropin Release from Rat Pituitary Tissue

Adrienne Fleckman, Jack Erlichman, Ulrich K. Schubart, Norman Fleischer

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The mechanisms by which TRH and membrane depolarization (40 mM K+) induce TSH release were explored by studying the effects of several calcium antagonists on TSH release and 45Ca2+ uptake by normal rat pituitaries. Trifluoperazine, a phenothiazine known to bind to calmodulin and block its action, inhibited TRH- and potassium-induced secretion. It also inhibited potassium-induced 45Ca2+ uptake, indicating that this agent can affect calcium movement in tissues as well as calcium action. The concentration of trifluoperazine required for half maximal inhibition of TRH- and K+-induced TSH release was 25–35 μM. In contrast, trifluoperazine potentiated 8-BrcAMP-induced TSH release, suggesting differences in the mechanisms of TRH and cAMP actions. D600 (α-isopropyl-α-[(N-methyl-N-homoveratryl)-γ-aminopropyl]-3, 4, 5-trimethoxyphenylacetonitrile hydrochloride) and phenytoin inhibited both TRH- and potassium-induced TSH release as well as potassium-induced 45Ca2+ uptake. D600 (1–100 μM) was slightly more effective in inhibiting potassium-induced release than in inhibiting TRH action. Phenytoin, on the other hand, was substantially more effective in blocking potassiumstimulated TSH release than TRH-induced release. Twenty micromolar phenytoin inhibited potassium-stimulated release by 80% whereas TRH-stimulated release was less than 40% inhibited. Since both D600 and phenytoin are known to inhibit sodium channels, studies with veratridine, a sodium channel activator, and tetrodotoxin, a sodium channel inhibitor, were performed. Veratridine (200 μM) stimulated TSH release 2-fold, and this effect was blocked by tetrodotoxin (6 μM). In contrast, tetrodotoxin had no effect on TRH-stimulated release suggesting that TRH does not directly involve activation of veratridine-sensitive sodium channels.

Original languageEnglish (US)
Pages (from-to)2072-2077
Number of pages6
JournalEndocrinology
Volume108
Issue number6
DOIs
StatePublished - Jun 1981

ASJC Scopus subject areas

  • Endocrinology

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