Fujimura T, Tamura K, Tsutsumi T, Yamamoto T, Nakamura K, Koibuchi Y, Kobayashi M, Yamaguchi O
Fujisawa Research Institute of America, Inc., Evanston, Illinois 60201, USA.
J Urol. 1999 Feb;161(2):680-5.
To investigate the presence of the beta3-adrenoceptor (beta3-AR) in human and rat detrusor muscle and the usefulness of beta3-AR agonists as drugs for the treatment of urinary frequency.
FK175, ethyl [(S)-8-[(R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-6,7,8,9-tetrah ydro-5H-benzocyclohepton-2-yloxy]acetate monohydrochloride monohydrate, was used as a beta3-AR selective agonist. The expression of beta-AR subtypes (beta1-, beta2-, beta3-AR) mRNA was investigated in rat and human detrusor muscle by RT-PCR. Beta3-AR agonist induced cyclic AMP (cAMP) levels were measured in rat detrusor muscle strips. The relaxation response produced by a beta3-AR agonist was measured in a KCl induced tonic contraction model in rat detrusor muscle strips. The effect of a beta3-AR agonist on urinary bladder function was investigated by cystometry using a conscious rat model of urinary frequency.
beta3-AR mRNA was substantially expressed in both rat and human detrusor muscles. The beta3-AR agonist, FK175 (10(-7) M), increased the cAMP level by 30% in rat detrusor muscle. In isolated rat detrusor muscle strips contracted with KCl, the beta3-AR agonist, FK175 (10(-8) to 10(-4) M), produced a concentration-dependent relaxation. Moreover, although the relaxation induced with FK175 was blocked by the non-selective beta-AR antagonist, bupranolol, it was unaffected by ether the beta1-AR selective antagonist, CGP 20712A, or the beta2-AR selective antagonist, ICI 118551, suggesting that FK175 induced the relaxation via the beta3-AR. Furthermore, in the rat model, the orally administered beta3-AR agonist, FK175 (10 mg./kg.) significantly increased bladder capacity with no change of micturition pressure or threshold pressure.
These results suggest that beta3-AR agonists may be effective in the treatment of urinary frequency.
研究β3 -肾上腺素能受体（β3 - AR）在人和大鼠逼尿肌中的存在情况，以及β3 - AR激动剂作为治疗尿频药物的有效性。
FK175，即盐酸乙[(S)-8-[(R)-2-(3-氯苯基)-2-羟乙氨基]-6,7,8,9-四氢-5H-苯并环庚-2-基氧基]乙酸一水合物，用作β3 - AR选择性激动剂。通过逆转录聚合酶链反应（RT-PCR）研究大鼠和人逼尿肌中β-肾上腺素能受体亚型（β1 -、β2 -、β3 - AR）mRNA的表达。在大鼠逼尿肌条中测量β3 - AR激动剂诱导的环磷酸腺苷（cAMP）水平。在大鼠逼尿肌条的氯化钾诱导的强直性收缩模型中测量β3 - AR激动剂产生的舒张反应。使用清醒大鼠尿频模型通过膀胱测压法研究β3 - AR激动剂对膀胱功能的影响。
β3 - AR mRNA在大鼠和人逼尿肌中均大量表达。β3 - AR激动剂FK175（10^(-7) M）使大鼠逼尿肌中的cAMP水平升高30%。在与氯化钾收缩的离体大鼠逼尿肌条中，β3 - AR激动剂FK175（10^(-8)至10^(-4) M）产生浓度依赖性舒张。此外，虽然FK175诱导的舒张被非选择性β-肾上腺素能受体拮抗剂布普萘洛尔阻断，但不受β1 - AR选择性拮抗剂CGP 20712A或β2 - AR选择性拮抗剂ICI 118551的影响，这表明FK175通过β3 - AR诱导舒张。此外，在大鼠模型中，口服β3 - AR激动剂FK175（10毫克/千克）显著增加膀胱容量，而排尿压力或阈压力无变化。
这些结果表明β3 - AR激动剂可能对治疗尿频有效。
