title: Analysis of agonism at functional prejunctional alpha 2-adrenoceptors of rat vas deferens using operational and null approaches.
abstract: The alpha 2-adrenoceptors located prejunctionally on the postganglionic neurons that innervate the smooth muscle of the prostatic portion of the rat vas deferens were examined. For this purpose, three imidazolidine derivatives (structurally related to clonidine) were studied for their effects on twitch contractions elicited by electrical field stimulation of this tissue. In this study, operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the alpha 2-adrenoceptor-mediated effects of clonidine (2-[2,6-dichlorophenylimino]imidazolidine) in stimulated vas deferens. The operational model provided an estimate of KA for clonidine which was not significantly different from the estimate obtained by using the nested hyperbolic method (null approach). The data indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors for clonidine. The estimates of apparent affinity for St-587 (2-[2-chloro-5-trifluoromethylphenylimino]imidazolidine) and St-591 (2-[2-chloro-5-methylphenylimino]imidazolidine) did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Further, estimates of the ratio of tau values for these partial agonists with respect to clonidine were numerically the same as those of their relative efficacies. Therefore, no limitations in the ability of the operational model to fit experimental data and provide reproducible estimates of affinity and efficacy have been revealed for agonists acting at prejunctional alpha 2-adrenoceptors.
authors.affiliation: Departament de Farmacologia i Psiquiatria, Facultat de Medicina, Universitat Autònoma de Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Sallés
authors.forename: J
authors.initials: J
authors.lastname: Giraldo
authors.forename: A
authors.initials: A
authors.lastname: Badia
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000465:Algorithms; D000478:Alkylation; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D014649:Vas Deferens / Q000187:drug effects / Q000294:innervation / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; C030655:St 587; C000470:EEDQ; D003000:Clonidine