Enhancement of histamine H1-receptor agonist activity by 1,4-dithiothreitol in guinea-pig cerebellum and cerebral cortex.
The disulphide bond-reducing agent 1,4-dithiothreitol (1 mM) produced a marked potentiation of histamine-stimulated accumulation of [3H]inositol phosphates 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 agonists 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 agonists 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 responses in guinea-pig cerebral cortex suggests that it is before the stage at which the receptor-effector pathways are shared by these two receptor systems.
D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008433:Mathematics; D008761:Methylhistamines / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*
D008761:Methylhistamines; D010716:Phosphatidylinositols; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D000242:Cyclic AMP; C026259:2-methylhistamine; D004229:Dithiothreitol