A difference in receptor mechanisms for muscarinic full and partial agonists.
Concentration-response curves of 4 muscarinic full agonists were progressively inhibited by 10 to 50-min treatments of the longitudinal muscle of guinea pig ileum with propylbenzilylcholine mustard (PrBCM, 3 x 10(-6) M). A 90-min treatment with PrBCM had no further significant inhibitory effect on their curves. The 50-min treatment with PrBCM (3 x 10(-6) M) completely inhibited the concentration-response curves of 6 partial agonists. The limiting effect of PrBCM observed on the concentration-response curves of the full agonists was not found on the curves of the partial agonists. These results suggest that there are two subtypes of M3-cholinoceptors, PrBCM-sensitive receptors and PrBCM-resistant ones. Pilocarpine, a partial agonist, shifted the concentration-response curve of carbachol, a full agonist, in a parallel fashion in the strips treated with PrBCM (3 x 10(-6) M) for 50 min, suggesting that an interaction of pilocarpine with PrBCM-resistant cholinoceptors does not induce contraction. The full agonists contract the longitudinal muscle through the interaction of two cholinoceptors, PrBCM-sensitive and -resistant ones, while the partial agonists produce the contraction through the activation of PrBCM-sensitive ones.
Takayanagi
I
I
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Harada
M
M
Koike
K
K
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000494:pharmacology*; D011438:Propylbenzilylcholine Mustard / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*
D010276:Parasympatholytics; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D011438:Propylbenzilylcholine Mustard