title: Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens.
abstract: The effects of irreversible alpha1-adrenoceptor antagonists, SZL-49 (an alkylating analogue of prazosin), dibenamine and benextramine on contractions to noradrenaline (NA) in longitudinal and circular muscle of human epididymal vas deferens were investigated. Competitive alpha1-adrenoceptor antagonists were also used to further characterize the alpha1-adrenoceptor subtype stimulated by NA in longitudinal and circular muscle. NA evoked concentration-dependent contractions of both muscle types (pD2; 5.4 and 5.2 respectively). The contraction of circular muscle was comparatively more sensitive than that of longitudinal muscle to pretreatment with SZL-49. In contrast, dibenamine or benextramine produced comparable effects in both muscle types. The relationship between receptor occupancy and contraction in either longitudinal or circular muscle was nonlinear, with half-maximal response requiring similar receptor occupancy (longitudinal muscle 14%, circular muscle 16%). Maximal response in both muscle types occurred with little or no receptor reserve (<10%). The competitive alpha1-adrenoceptor antagonists produced dextral shifts of the dose-response curves to NA in longitudinal and circular muscle. The inhibitory potencies, estimated from the apparent pKB values were significantly different in longitudinal and circular muscle respectively for either WB 4101 (pKB, 8.6 and 9.5) or RS-17053 (pKB, 7.1 and 9.0) but not for Rec 15/2739 (pKB, 9.2 and 9.8) or HV 723 (pKB, 8.3 and 8.4). In conclusion, the potency profile of the competitive alpha1-adrenoceptor antagonists and the lack of different receptor reserves for NA in the muscle types suggest that the discriminatory effects of SZL-49 is primarily due to a predominance of the alpha1L-adrenoceptor subtype in longitudinal muscle and alpha1A-subtype in circular muscle.
authors.affiliation: GKT School of Biomedical Sciences, King's College London, Guy's Campus, London SE1 1UL, UK.
authors.forename: Nnaemeka I B
authors.initials: NI
authors.lastname: Amobi
authors.forename: John
authors.initials: J
authors.lastname: Guillebaud
authors.forename: A V
authors.initials: AV
authors.lastname: Kaisary
authors.forename: Eileen
authors.initials: E
authors.lastname: Turner
authors.forename: I Christopher H
authors.initials: IC
authors.lastname: Smith
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D003538:Cystamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003983:Dibenzylchlorethamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; C051307:SZL 49; D003983:Dibenzylchlorethamine; C029998:benextramine; D003538:Cystamine; D009638:Norepinephrine; D011224:Prazosin