Enhancement of Histamine H1-Receptor Agonist Activity by 1,4-Dithiothreitol in Guinea-Pig Cerebellum and Cerebral Cortex

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Abstract
The disulphide bond-reducing agent 1,4-dithiothreitol (1 mM) produced a marked potentiation of histamine-stimulated accumulation of [3H]inositol phosphate in lithium-treated slices of guinea-pig cerebellum and cerebral cortex. This was seen as a parallel shift of the concentration-response curve for histamine to lower agonist concentrations with no significant effect on the maximal response or Hill coefficient. Dithiothreitol similarly potentiated the augmentation of adenosine-stimulated cyclic AMP accumulation elicited by histamine in guinea-pig cerebral cortex. Studies with partial agonist suggested that this potentiating effect was associated with an increase in agonist efficacy rather than a change in agonist binding affinity. Thus, dithiothreitol increased the maximal accumulation of [3H]inositol phosphates produced by both 2-pyridylethylamine and 2-methylhistamine, which appeared to act as partial agonist in guinea-pig cerebral cortex. Dithiothreitol similarly increased the maximal extent of the augmentation of adenosine-stimulated accumulation of cyclic AMP produced by 2-methylhistamine. The site of action of dithiothreitol is not known; however, a comparison of the effect of dithiothreitol on muscarinic and histamine H1-receptor-mediated phosphoinositide response in guinea-pig cerebral cortex suggest that it is before the stage at which the receptor-effector pathways are shared by these two receptor systems.