Rouget Céline, Rekik Moèz, Camparo Philippe, Botto Henry, Rischmann Pascal, Lluel Philippe, Palea Stefano, Westfall Timothy D
UROsphere, Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex 09, France.
Foch Hospital, Anatomy and Cytopathology Department, 92151 Suresnes Cedex, France.
Pharmacol Res. 2014 Feb;80:14-20. doi: 10.1016/j.phrs.2013.12.006. Epub 2013 Dec 28.
Activation of β3-adrenoceptors has been shown to have a direct relaxant effect on urinary bladder smooth muscle from both rats and humans, however there are very few studies investigating the effects of β3-adrenoceptor agonists on nerve-evoked bladder contractions. Therefore in the current study, the role of β3-adrenoceptors in modulating efferent neurotransmission was evaluated. The effects of β3-adrenoceptor agonism on neurogenic contractions induced by electrical field stimulation (EFS) were compared with effects on contractions induced by exogenous acetylcholine (Ach) and αβ-methylene adenosine triphosphate (αβ-meATP) in order to determine the site of action. Isoproterenol inhibited EFS-induced neurogenic contractions of human bladder (pD2=6.79; Emax=65%). The effect of isoproterenol was selectively inhibited by the β3-adrenoceptor antagonist L-748,337 (pKB=7.34). Contractions induced by exogenous Ach (0.5-1μM) were inhibited 25% by isoproterenol (3μM) while contractions to 10Hz in the same strip were inhibited 67%. The selective β3-adrenoceptor agonist CL-316,243 inhibited EFS-induced neurogenic contractions of rat bladder (pD2=7.83; Emax=65%). The effects of CL-316,243 were inhibited in a concentration dependent manner by L-748,337 (pA2=6.42). Contractions induced by exogenous Ach and αβ-meATP were significantly inhibited by CL-316,243, 29% and 40%, respectively. These results demonstrate that the activation of β3-adrenoceptors inhibits neurogenic contractions of both rat and human urinary bladder. Contractions induced by exogenously applied parasympathetic neurotransmitters are also inhibited by β3-agonism however the effect is clearly less than on neurogenic contractions (particularly in human), suggesting that in addition to a direct effect on smooth muscle, activation of prejunctional β3-adrenoceptors may inhibit neurotransmitter release.
β3肾上腺素能受体的激活已被证明对大鼠和人类的膀胱平滑肌具有直接的舒张作用，然而，很少有研究调查β3肾上腺素能受体激动剂对神经诱发的膀胱收缩的影响。因此，在本研究中，评估了β3肾上腺素能受体在调节传出神经传递中的作用。将β3肾上腺素能受体激动对电场刺激（EFS）诱导的神经源性收缩的影响与对外源性乙酰胆碱（Ach）和αβ-亚甲基三磷酸腺苷（αβ-meATP）诱导的收缩的影响进行比较，以确定作用部位。异丙肾上腺素抑制人膀胱EFS诱导的神经源性收缩（pD2=6.79；Emax=65%）。β3肾上腺素能受体拮抗剂L-748,337选择性抑制异丙肾上腺素的作用（pKB=7.34）。外源性Ach（0.5-1μM）诱导的收缩被异丙肾上腺素（3μM）抑制25%，而同一条带中10Hz刺激诱导的收缩被抑制67%。选择性β3肾上腺素能受体激动剂CL-316,243抑制大鼠膀胱EFS诱导的神经源性收缩（pD2=7.83；Emax=65%）。L-748,337以浓度依赖性方式抑制CL-31,243的作用（pA2=6.42）。外源性Ach和αβ-meATP诱导的收缩分别被CL-316,243显著抑制29%和40%。这些结果表明，β3肾上腺素能受体的激活抑制大鼠和人类膀胱的神经源性收缩。β3激动剂也抑制外源性应用的副交感神经递质诱导的收缩，然而，其作用明显小于对神经源性收缩的作用（特别是在人类中），这表明除了对平滑肌的直接作用外，节前β3肾上腺素能受体的激活可能抑制神经递质释放。
