Clouse Angela K, Riedel Erin, Hieble J Paul, Westfall Timothy D
Department of Urogenital Biology, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, P.O. Box 1539, 709 Swedeland Road, King of Prussia, PA 19406 USA.
Eur J Pharmacol. 2007 Nov 14;573(1-3):184-9. doi: 10.1016/j.ejphar.2007.06.016. Epub 2007 Jun 27.
Recent evidence supports a role for beta(3)-adrenoceptors in human non-pregnant and pregnant myometrium. The present study was designed to characterize the pharmacology of beta-adrenoceptors involved in the function of non-pregnant rat myometrium by comparison of the activity of several beta-adrenoceptor agonists and antagonists in isolated rat uterus and urinary bladder. Contractions of myometrial and detrusor strips were induced by adding 1 nM oxytocin and 15 mM KCl respectively. Cumulative concentration-response curves to the selective beta(3)-adrenoceptor agonists, CL 316243 and BRL 37344 and the selective beta(2)-adrenoceptor agonist ritodrine were obtained in the presence and absence of the selective beta(2)-adrenoceptor antagonist ICI 118551 and the non-selective beta-adrenoceptor antagonist bupranolol. Both BRL 37344 (pD(2)=6.79+/-0.09) and ritodrine (pD(2)=6.89+/-0.19) produced potent inhibition of oxytocin-induced contractions in myometrial strips; CL 316243 was inactive at concentrations up to 10 microM. Concentration effect curves to both BRL 37344 and ritodrine were shifted (10 to 30-fold) to the right in the presence of ICI 118551 (10 nM). BRL 37344 (pD(2)=8.51+/-0.21) and CL 316243 (pD(2)=8.61+/-0.24) produced potent inhibition of detrusor strips, while ritodrine was almost 100-fold less potent (pD(2)=5.83+/-0.17). The response to all agonists was significantly attenuated by pretreatment with bupranolol (10 microM), but only ritodrine was affected by ICI 118551 (1 microM). These results demonstrate that relaxation of rat myometrium is mediated by beta(2)-adrenoceptors while, consistent with previous reports, the beta(3)-subtype is primarily responsible for relaxation of rat detrusor.
最近的证据支持β(3)-肾上腺素能受体在人类非妊娠及妊娠子宫肌层中发挥作用。本研究旨在通过比较几种β-肾上腺素能受体激动剂和拮抗剂在离体大鼠子宫和膀胱中的活性，来表征参与非妊娠大鼠子宫肌层功能的β-肾上腺素能受体的药理学特性。分别加入1 nM缩宫素和15 mM氯化钾诱导子宫肌层和逼尿肌条收缩。在存在和不存在选择性β(2)-肾上腺素能受体拮抗剂ICI 118551和非选择性β-肾上腺素能受体拮抗剂布普萘洛尔的情况下，获得对选择性β(3)-肾上腺素能受体激动剂CL 316243和BRL 37344以及选择性β(2)-肾上腺素能受体激动剂利托君的累积浓度-反应曲线。BRL 37344（pD(2)=6.79±0.09）和利托君（pD(2)=6.89±0.19）均能有效抑制子宫肌层条中缩宫素诱导的收缩；CL 316243在高达10 μM的浓度下无活性。在存在ICI 118551（10 nM）的情况下，BRL 37344和利托君的浓度效应曲线均右移（10至30倍）。BRL 37344（pD(2)=8.51±0.21）和CL 316243（pD(2)=8.61±0.24）能有效抑制逼尿肌条，而利托君的效力几乎低100倍（pD(2)=5.83±0.17）。用布普萘洛尔（10 μM）预处理后，对所有激动剂的反应均显著减弱，但只有利托君受ICI 118551（1 μM）影响。这些结果表明，大鼠子宫肌层的舒张由β(2)-肾上腺素能受体介导，而与先前报道一致，β(3)亚型主要负责大鼠逼尿肌的舒张。
