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CARDIOVASCULAR

Identification of -1L Adrenoceptor in Rabbit Ear Artery

Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Matsuoka, Fukui, Japan

The -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] (-1A and -1L AR-selective agonist) was competitively antagonized with low affinities by prazosin, RS-17053 [N-[2-(2-cyclopropylmethoxyphenoxy) ethyl]-5-chloro-,-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 -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 -1L ARs, whereas the response to noradrenaline was produced through two distinct -1 AR subtypes (presumably -1B and -1L ARs). In binding studies with intact segments of rabbit ear artery, [³H]KMD-3213 bound with high affinity (pK_D = 9.7) to -1 ARs, which were subdivided by prazosin, RS-17053, and 5-methylurapidil into two subtypes (-1A and -1L ARs). In contrast, [³H]prazosin binding sites in ear artery segments (pK_D = 9.8) were identified as -1A and -1B ARs. In conventional binding studies using isolated rabbit ear artery microsomal membranes, [³H]KMD-3213 binding sites were identified as -1A ARs with high affinities for prazosin, RS-17053, and 5-methylurapidil. Our study indicates that an -1L AR having a unique pharmacological profile coexists with -1A and -1B ARs in rabbit ear artery and can be identified either functionally or by binding studies using intact tissues but not microsomal membrane preparations.

Address correspondence to: Ikunobu Muramatsu, Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Matsuoka, Fukui 910-1193, Japan. E-mail: muramatu{at}fmsrsa.fukui-med.ac.jp

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