title: Pharmacological profile of KUL-7211, a selective beta-adrenoceptor agonist, in isolated ureteral smooth muscle.
abstract: Since, in the human ureter, both beta(2)- and beta(3)-adrenoceptors mediate adrenergic-stimulation-induced relaxation, selective beta(2)-/beta(3)-adrenoceptor agonists might prove clinically useful for relieving ureteral colic and promoting stone passage. We evaluated the beta-adrenoceptor subtype selectivity and ureteral-relaxing efficacy of (-)-2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amin] ethyl)phenyloxy]acetic acid (KUL-7211), a new beta-adrenoceptor agonist, in vitro. In rat isolated organs, its selectivities, for inhibition of spontaneous uterine contraction (mediated via beta(2)-adrenergic stimulation) and inhibition of colonic contraction (via beta(3)-adrenergic stimulation) versus increase in atrial rate (via beta(1)-adrenergic stimulation), were 56.3 and 242.2, respectively. KUL-7211 relaxed 80-mM-KCl-induced tonic contractions in both rabbit (pD(2) value: 5.86 +/- 0.13, whose ureteral relaxation is mediated via beta(2)-adrenergic stimulation) and canine (pD(2) value: 6.52 +/- 0.16, via beta(3)-adrenergic stimulation) isolated ureters in a concentration-dependent manner. These KUL-7211-induced relaxing effects were antagonized by ICI-118,551 (selective beta(2)-adrenoceptor antagonist, pK(B) value: 8.91 +/- 0.24) in the rabbit ureter and by bupranolol (non-selective beta-adernoceptor antagonist, pK(B) value: 6.85 +/- 0.12) in the canine ureter. KUL-7211 also reduced the spontaneous rhythmic contraction in a canine ureteral spiral preparation in a concentration-dependent manner, the pD(2) value being 6.83 +/- 0.20. These data clearly demonstrate that KUL-7211 selectively stimulates both ureteral beta(2)- and beta(3)-adrenoceptors and potently relaxes ureteral smooth muscle. KUL-7211 may be a novel and useful medication for relieving ureteral colic and promoting stone passage in urolithiasis patients.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co, Ltd, Nagano, Japan. yoshitaka_tomiyama@pharm.kissei.co.jp
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.forename: Kohichi
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Akiyama
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shibata
authors.forename: Masuo
authors.initials: M
authors.lastname: Akahane
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014513:Ureter / Q000187:drug effects* / Q000502:physiology
chemical_list: D000085:Acetates; D000318:Adrenergic beta-Agonists; C484908:KUL7211; D011943:Receptors, Adrenergic, beta