Article date: February 1989
By: Lesley A. Joels, Alan H. Drummond in Volume 96, Issue 2, pages 450-456
Seven benzodiazepines were investigated for their ability to interact with receptors for thyrotropin‐releasing hormone (TRH) on GH3 and GH4C1 pituitary tumour cells.
Midazolam and chlordiazepoxide were the most potent inhibitors of TRH‐induced [3H]‐inositol phosphate formation with Ki values in the low micromolar range. The antagonism was competitive in nature and was increased in potency at sub‐physiological temperatures.
None of the agents examined antagonized bombesin‐induced [3H]‐inositol phosphate formation in GH4C1 cells.
While the ability of benzodiazepines to interact with the GABA receptor‐chloride channel ionophore is markedly stereospecific, little difference was evident in the ability of (+)− and (−)−4‐methylmidazolam (Ro 21–5656 and Ro 21–5657) to compete with TRH at its receptor.
Recently it has been suggested that, in contrast to phosphatidylinositol hydrolysis, the TRH‐induced breakdown of phosphatidylinositol polyphosphates is transient in clonal pituitary cells. Addition of chlordiazepoxide to TRH‐stimulated GH3 cells up to 60 min after initiating the reaction leads, however, to an immediate decline in the cellular content of inositol trisphosphate. This indicates that TRH‐induced phosphatidylinositol 4,5‐bisphosphate hydrolysis is not transient.
Seven benzodiazepines were investigated for their ability to interact with receptors for thyrotropin‐releasing hormone (TRH) on GH3 and GH4C1 pituitary tumour cells.
Midazolam and chlordiazepoxide were the most potent inhibitors of TRH‐induced [3H]‐inositol phosphate formation with Ki values in the low micromolar range. The antagonism was competitive in nature and was increased in potency at sub‐physiological temperatures.
None of the agents examined antagonized bombesin‐induced [3H]‐inositol phosphate formation in GH4C1 cells.
While the ability of benzodiazepines to interact with the GABA receptor‐chloride channel ionophore is markedly stereospecific, little difference was evident in the ability of (+)− and (−)−4‐methylmidazolam (Ro 21–5656 and Ro 21–5657) to compete with TRH at its receptor.
Recently it has been suggested that, in contrast to phosphatidylinositol hydrolysis, the TRH‐induced breakdown of phosphatidylinositol polyphosphates is transient in clonal pituitary cells. Addition of chlordiazepoxide to TRH‐stimulated GH3 cells up to 60 min after initiating the reaction leads, however, to an immediate decline in the cellular content of inositol trisphosphate. This indicates that TRH‐induced phosphatidylinositol 4,5‐bisphosphate hydrolysis is not transient.
DOI: 10.1111/j.1476-5381.1989.tb11837.x
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