title: The potency of KUL-7211, a selective ureteral relaxant, in isolated canine ureter: comparison with various spasmolytics.
abstract: We compared the potency of a selective ureteral relaxant KUL-7211 (beta(2)/beta(3)-adrenoceptor agonist; (-)-2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenyloxy]acetic acid) with those of various spasmolytics on contractions in isolated canine ureteral preparations. Drug effects were evaluated on the tonic contraction induced by KCl (80 mM) and on spontaneous, 1x10(-5) M phenylephrine-, and 1x10(-6) M PGF(2alpha)-induced rhythmic contractions in isolated canine ureteral preparations using a functional experimental technique. The potencies (pD(2) value) of the following drugs were compared: KUL-7211, tamsulosin (an alpha(1A/1D)-adrenoceptor antagonist), prazosin (an alpha(1)-adrenoceptor antagonist), verapamil (a Ca(2+)-channel blocker), butylscopolamine (a nonselective muscarinic antagonist), and papaverine (a phosphodiesterase inhibitor). The rank order of relaxing potencies against KCl-induced tonic contraction was KUL-7211 (6.60)>tamsulosin(5.90)>verapamil(5.70)>papaverine(4.88)>prazosin (4.54). The rank order of potencies for reductions in spontaneous rhythmic contractions was KUL-7211 (6.80)>verapamil(6.12)>papaverine(5.05). Conversely, high concentrations of the two alpha-adrenoceptor antagonists (tamsulosin and prazosin) and of butylscopolamine enhanced the spontaneous contractions, although at low concentrations (up to 1x10(-6) M) they had no significant effects. For suppression of spasmogen-induced rhythmic contractions, the rank order of potencies was, against phenylephrine-induced contractions: KUL-7211 (6.95)>tamsulosin(6.26)>prazosin(5.68)>verapamil(5.64)>papaverine (5.03), and against PGF(2alpha)-induced contractions: KUL-7211 (7.05)>verapamil(6.70)>papaverine (5.27). Our results suggest that in dogs, the beta(2)/beta(3)-adrenoceptor agonist KUL-7211 is the most efficacious ureteral relaxant among the spasmolytics tested against various contractions. Possibly, KUL-7211 might be useful for promoting stone passage and relieving ureteral colic in urolithiasis patients.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Company Ltd., 4365-1, Kashiwabara, Hotaka, Nagano 399-8304, Japan. isao_wanajo@pharm.kissei.co.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Wanajo
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Mariko
authors.initials: M
authors.lastname: Tadachi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kobayashi
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
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003085:Colic / Q000517:prevention & control; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000145:classification / Q000502:physiology; D014513:Ureter / Q000187:drug effects* / Q000502:physiology*; D014515:Ureteral Diseases / Q000517:prevention & control; D014517:Ureteral Obstruction / Q000517:prevention & control; D014545:Urinary Calculi / Q000188:drug therapy
chemical_list: D000085:Acetates; D000318:Adrenergic beta-Agonists; C484908:KUL7211; D010276:Parasympatholytics; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D011189:Potassium Chloride; D015237:Dinoprost