Wanajo Isao, Tomiyama Yoshitaka, Tadachi Mariko, Kobayashi Mamoru, Yamazaki Yoshinobu, Kojima Masami, Shibata Nobuo
Central Research Laboratory, Kissei Pharmaceutical Company Ltd., 4365-1, Kashiwabara, Hotaka, Nagano 399-8304, Japan.
Urol Res. 2005 Dec;33(6):409-14. doi: 10.1007/s00240-005-0475-5. Epub 2005 Aug 25.
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.
我们在离体犬输尿管制备物中，比较了选择性输尿管松弛剂KUL-7211（β₂/β₃肾上腺素能受体激动剂；(-)-2-[4-(2-{[(1S,2R)-2-羟基-2-(4-羟基苯基)-1-甲基乙基]氨基}乙基)苯氧基]乙酸）与各种解痉药对收缩的效力。使用功能实验技术，在离体犬输尿管制备物中，评估了药物对由氯化钾（80 mM）诱导的强直性收缩以及对自发的、1×10⁻⁵ M去氧肾上腺素和1×10⁻⁶ M前列腺素F₂α诱导的节律性收缩的作用。比较了以下药物的效力（pD₂值）：KUL-7211、坦索罗辛（一种α₁A/₁D肾上腺素能受体拮抗剂）、哌唑嗪（一种α₁肾上腺素能受体拮抗剂）、维拉帕米（一种钙通道阻滞剂）、丁溴东莨菪碱（一种非选择性毒蕈碱拮抗剂）和罂粟碱（一种磷酸二酯酶抑制剂）。对氯化钾诱导的强直性收缩的松弛效力排序为：KUL-7211（6.60）>坦索罗辛（5.90）>维拉帕米（5.70）>罂粟碱（4.88）>哌唑嗪（4.54）。对自发节律性收缩减弱的效力排序为：KUL-7211（6.80）>维拉帕米（6.12）>罂粟碱（5.05）。相反，两种α肾上腺素能受体拮抗剂（坦索罗辛和哌唑嗪）以及丁溴东莨菪碱的高浓度会增强自发收缩，尽管在低浓度（高达1×10⁻⁶ M）时它们没有显著作用。对于抑制致痉剂诱导的节律性收缩，对去氧肾上腺素诱导的收缩的效力排序为：KUL-7211（6.95）>坦索罗辛（6.26）>哌唑嗪（5.68）>维拉帕米（5.64）>罂粟碱（5.03），对前列腺素F₂α诱导的收缩的效力排序为：KUL-7211（7.05）>维拉帕米（6.70）>罂粟碱（5.27）。我们的结果表明，在犬中，β₂/β₃肾上腺素能受体激动剂KUL-7211是所测试的各种解痉药中对各种收缩最有效的输尿管松弛剂。可能，KUL-7211对促进尿路结石患者的结石排出和缓解输尿管绞痛可能有用。
