Antagonism by the tetramine disulfide benextramine of the inhibitory effects mediated by prejunctional alpha₂-adrenoceptors and by postjunctional histamine H₂ receptors in the mouse vas deferens

The actions of benextramine, which blocks postjunctional alpha-adrenoceptors noncompetitively and irreversibly (non equilibrium type) on prejunctional alpha-adrenoceptors (alpha₂) and postjunctional histamine H₂ receptors, were studied in the mouse vas deferens, using clonidine and histamine, respectively, as the agonists. Both agonists caused a dose-related inhibition of the electrically evoked twitch responses, an inhibition that their respective antagonists (yohimbine or phentolamine, and cimetidine) antagonized competitively. Benextramine, however, antagonized the agonists' inhibitory effect noncompetitively. At the concentrations used, while clonidine or yohimbine and phentolamine protected the prejunctional alpha-adrenoceptors (alpha₂) against the benextramine noncompetitive blockade, histamine or cimetidine failed to protect the histamine H₂-receptor against benextramine blockade. Therefore, although benextramine acts prejunctionally to block the alpha₂-adrenoreceptors in the mouse vas deferens either by interacting directly with the same site as clonidine or yohimbine and phentolamine, or allosterically with a site close to it, it does not appear to act irreversibly, either directly or allosterically, with the same site as histamine or cimetidine. The mechanism by which benextramine blocks the histamine-induced inhibition of the electrically evoked twitch response in the mouse vas deferens remains to be established.