title: Identification of alpha-1L adrenoceptor in rabbit ear artery.
abstract: The alpha-1L adrenoceptor (AR) was identified in rabbit ear artery by both functional and ligand binding studies. In functional studies using arterial rings, the contractile response to NS-49 [(R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluorometh-anesulfonanilide hydrochloride] (alpha-1A and alpha-1L AR-selective agonist) was competitively antagonized with low affinities by prazosin, RS-17053 [N-[2-(2-cyclopropylmethoxyphenoxy) ethyl]-5-chloro-alpha,alpha-dimethyl-1H-indole-3-ethamine hydrochloride], and 5-methylurapidil but with high affinities by tamsulosin and KMD-3213 [(-)-1-(3-hydroxypropyl)-5-[(2R)-2-([2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide]. In contrast, the response to noradrenaline (nonselective alpha-1 AR agonist) was inhibited noncompetitively by these antagonists (except 5-methylurapidil) with Schild slopes different from unity. These results suggest that the response to NS-49 was mediated predominantly via alpha-1L ARs, whereas the response to noradrenaline was produced through two distinct alpha-1 AR subtypes (presumably alpha-1B and alpha-1L ARs). In binding studies with intact segments of rabbit ear artery, [3H]KMD-3213 bound with high affinity (pKD=9.7) to alpha-1 ARs, which were subdivided by prazosin, RS-17053, and 5-methylurapidil into two subtypes (alpha-1A and alpha-1L ARs). In contrast, [3H]prazosin binding sites in ear artery segments (pKD = 9.8) were identified as alpha-1A and alpha-1B ARs. In conventional binding studies using isolated rabbit ear artery microsomal membranes, [3H]KMD-3213 binding sites were identified as alpha-1A ARs with high affinities for prazosin, RS-17053, and 5-methylurapidil. Our study indicates that an alpha-1L AR having a unique pharmacological profile coexists with alpha-1A and alpha-1B ARs in rabbit ear artery and can be identified either functionally or by binding studies using intact tissues but not microsomal membrane preparations.
authors.affiliation: Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Matsuoka, Fukui 910-1193, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hiraizumi-Hiraoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Fumiko
authors.initials: F
authors.lastname: Suzuki
authors.forename: Ikunobu
authors.initials: I
authors.lastname: Muramatsu
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004423:Ear / Q000033:anatomy & histology*; D007211:Indoles / Q000378:metabolism; D008297:Male; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000302:isolation & purification* / Q000378:metabolism*; D014316:Tritium
chemical_list: D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D018340:Receptors, Adrenergic, alpha-1; D014316:Tritium; C095285:silodosin; D011224:Prazosin