Antagonism by imidazoline-type drugs of muscarinic and other receptors in the guinea-pig ileum.
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 (KB) of 3.6 microm for the antagonist was calculated. At higher concentrations, 3 x 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 alpha-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.
Salazar-Bookaman
M M
MM
Department of Pharmacology, College of Pharmacy, Universidad Central de Venezuela, Caracas, Venezuela.
Miller
D D
DD
Patil
P N
PN
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D048288:Imidazolines / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010109:Oxymetazoline / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology
D018679:Cholinergic Agonists; D048288:Imidazolines; D018727:Muscarinic Antagonists; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D012701:Serotonin; D006632:Histamine; D010109:Oxymetazoline; D002217:Carbachol; D008729:Methoxamine