title: Contractile actions of imidazoline alpha-adrenoceptor agonists and effects of noncompetitive alpha1-adrenoceptor antagonists in human vas deferens.
abstract: The contractile actions of imidazoline alpha-adrenoceptor agonists were investigated in human vas deferens longitudinal and circular muscle. The effects of phenoxybenzamine were studied in comparison to dibenamine and SZL-49 (4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-bicyclo[2,2,2]octa-2,5-dienylcarbonyl-2-piperazine), an alkylating prazosin analogue that discriminates between alpha(1H)- and alpha(1L)-adrenoceptor subtypes. The imidazoline alpha-adrenoceptor agonist, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide), was a potent agonist (pD(2); longitudinal muscle 6.9, circular muscle 6.4) and cirazoline a partial agonist (pD(2); longitudinal muscle 6.1, circular muscle 5.1). Oxymetazoline was less effective, indanidine and clonidine were ineffective. SZL-49 produced a differential inhibition of contractions evoked by A-61603 in circular (alpha(1H)) compared to longitudinal (alpha(1L)) muscle and phenoxybenzamine had the opposite effect. Dibenamine inhibited the contractions comparably in both muscle types and analyses of its partial alkylation of receptors yielded identical estimates of equilibrium dissociation constant (pK(d)) for A-61603 in longitudinal (5.82) and circular (5.84) muscle. Receptor occupancy-response relationships revealed that whilst the muscle types are not different in receptor reserves for A-61603, contraction to the potent imidazoline is more efficiently coupled in longitudinal than in circular muscle. This underlies the markedly different responsiveness of the muscle types to cirazoline or oxymetazoline (alpha-adrenoceptor agonists with lower efficacies relative to A-61603). The differential inhibitory actions of phenoxybenzamine and SZL-49 are discussed.
authors.affiliation: GKT School of Biomedical Sciences, King's College, Guy's Campus, London SE1 1UL, UK.
authors.forename: Nnaemeka
authors.initials: N
authors.lastname: Amobi
authors.forename: John
authors.initials: J
authors.lastname: Guillebaud
authors.forename: Amir
authors.initials: A
authors.lastname: Kaisary
authors.forename: R W
authors.initials: RW
authors.lastname: Lloyd-Davies
authors.forename: Eileen
authors.initials: E
authors.lastname: Turner
authors.forename: I Christopher H
authors.initials: IC
authors.lastname: Smith
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D003983:Dibenzylchlorethamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010109:Oxymetazoline / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology
chemical_list: C094643:A 61603; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; D010643:Phenoxybenzamine; C051307:SZL 49; D003983:Dibenzylchlorethamine; D010109:Oxymetazoline; C014282:cirazoline; D009638:Norepinephrine; D011224:Prazosin