Effect of trifluoperazine, D600, and phenytoin on depolarization- and thyrotropin-releasing hormone-induced thyrotropin release from rat pituitary tissue

A. Fleckman, J. Erlichman, U. K. Schubart, N. Fleischer

Research output: Contribution to journalArticle

48 Citations (Scopus)

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-Br-cAMP-induced TSH release, suggesting differences in the mechanisms of TRH and cAMP actions. D600 (α-isopropyl-α-[(N-methyl-N-homoveratryl)-γ-amino-propyl]-3,4,5-trimethox yphenylacetonitrile 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 potassium-stimulated 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
StatePublished - 1981

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Gallopamil
Trifluoperazine
Thyrotropin-Releasing Hormone
Phenytoin
Thyrotropin
Potassium
Veratridine
Tetrodotoxin
Sodium Channels
Calcium
Sodium Channel Agonists
Sodium Channel Blockers
Calmodulin
Membranes

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Effect of trifluoperazine, D600, and phenytoin on depolarization- and thyrotropin-releasing hormone-induced thyrotropin release from rat pituitary tissue. / Fleckman, A.; Erlichman, J.; Schubart, U. K.; Fleischer, N.

In: Endocrinology, Vol. 108, No. 6, 1981, p. 2072-2077.

Research output: Contribution to journalArticle

Fleckman, A. ; Erlichman, J. ; Schubart, U. K. ; Fleischer, N. / Effect of trifluoperazine, D600, and phenytoin on depolarization- and thyrotropin-releasing hormone-induced thyrotropin release from rat pituitary tissue. In: Endocrinology. 1981 ; Vol. 108, No. 6. pp. 2072-2077.
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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-Br-cAMP-induced TSH release, suggesting differences in the mechanisms of TRH and cAMP actions. D600 (α-isopropyl-α-[(N-methyl-N-homoveratryl)-γ-amino-propyl]-3,4,5-trimethox yphenylacetonitrile 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 potassium-stimulated 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.",
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