Antagonism by imidazoline – type drugs of muscarinic and other receptors in the guinea-pig ileum

Summary

1 Several imidazolines were examined for the antagonism of muscarinic (M₃) and other receptors on the isolated ileum of guinea-pig. The effect of the muscarinic agonist, carbachol was competitively antagonized by oxymetazoline at 10⁻⁵ m. A dissociation constant (K_B) of 3.6 μm for the antagonist was calculated. At higher concentrations, 3 × 10⁻⁵ and 10⁻⁴ m, of the antagonist, the agonist dose–response curve was shifted to the right with a decrease in the maximum effect. Thus, a non-competitive block occurred at higher concentrations of oxymetazoline. Blockade of histamine H, and serotonin receptor-mediated responses by oxymetazoline were also of a non-competitive type.

2 Naphazoline at 10⁻⁴ m shifted the dose-response curves of carbachol and serotonin to the right by two- and 15-fold, respectively. The maximum contraction of the agonist was not affected. Tolazoline also had a weak antihistaminic activity. At similar concentration; tetrahydrozoline clonidine and phentolamine at 10⁻⁵ m produced two-, three- and four-fold shift of the carbachol dose–response curve without significant changes in the maxima. Neither methoxamine, p-amino-clonidine nor cimetidine blocked the responses of carbachol.

3 The isosteric nature of the α-adrenoceptor agonist, oxymetazoline and some imidazolines with carbachol, in part, explains its molecular competition at the muscarinic M₃ receptor of the guinea-pig ileum. Surprisingly, contractile effects of carbachol (M₃), histamine (H₁) or serotonin (5HT₃/5HT₄) were not influenced by methoxamine, tetrahydrozoline, p-amino clonidine and cimetidine.