TY - JOUR T1 - Comparison of the Antimuscarinic Action of <em>p</em>-Fluorohexahydrosiladifenidol in Ileal and Tracheal Smooth Muscle JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 592 LP - 600 DO - 10.1124/jpet.104.074898 VL - 312 IS - 2 AU - Frederick J. Ehlert AU - Jake Ching-Hsuan Hsu AU - Kevin Leung AU - Alex G. Lee AU - Darakhshanda Shehnaz AU - Michael T. Griffin Y1 - 2005/02/01 UR - http://jpet.aspetjournals.org/content/312/2/592.abstract N2 - We investigated the ability of the muscarinic antagonist p-fluorohexahydrosiladifenidol to inhibit muscarinic agonist-induced contractions and phosphoinositide hydrolysis in the guinea pig ileum and trachea. This antagonist displayed higher potency at blocking oxotremorine-M-induced contractions of the ileum compared with those of the trachea. When estimated using a simple model for competitive antagonism, the observed dissociation constant of p-fluorohexahydrosiladifenidol exhibited approximately 12-fold higher potency in the ileum compared with the trachea. We also investigated the ability of p-fluorohexahydrosiladifenidol to affect the inhibition of contraction caused by the known competitive muscarinic antagonist atropine. Using resultant analysis to analyze this interaction, we found that the true dissociation constant of p-fluorohexahydrosiladifenidol for competitively antagonizing oxotremorine-M-induced contractions in the ileum exhibited significantly lower potency than when calculated assuming a simple competitive model. In contrast, resultant analysis showed little difference between the true and observed potencies of p-fluorohexahydrosiladifenidol for antagonizing oxotremorine-M-induced contractions in the trachea. Using a simple competitive model, we found little difference in the observed dissociation constant of p-fluorohexahydrosiladifenidol for antagonizing oxotremorine-M-induced phosphoinositide hydrolysis in guinea pig ileum and bovine trachea. We also noted that p-fluorohexahydrosiladifenidol (0.3–1.0 μM) moderately inhibited histamine-induced contractions of ileum but not of trachea. Our results suggest that p-fluorohexahydrosiladifenidol does not discriminate markedly between M3 muscarinic receptors in the ileum and trachea and that it may posses a more potent, nonmuscarinic inhibitory effect on contraction in the ileum. ER -