Recio Paz, Barahona María Victoria, Orensanz Luis M, Bustamante Salvador, Martínez Ana Cristina, Benedito Sara, García-Sacristán Albino, Prieto Dolores, Hernández Medardo
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Br J Pharmacol. 2009 May;157(2):271-80. doi: 10.1111/j.1476-5381.2009.00144.x. Epub 2009 Mar 20.
5-Hydroxytryptamine (5-HT) is one of the inhibitory mediators in the urinary bladder outlet region. Here we investigated mechanisms involved in 5-HT-induced relaxations of the pig bladder neck.
Urothelium-denuded strips of pig bladder were mounted in organ baths for isometric force recordings of responses to 5-HT and electrical field stimulation (EFS).
After phenylephrine-induced contraction, 5-HT and 5-HT receptor agonists concentration-dependently relaxed the preparations, with the potency order: 5-carboxamidotryptamine (5-CT) > 5-HT = RS67333 > (+/-)-8-hydroxy-2-dipropylaminotetralinhydrobromide > m-chlorophenylbiguanide > alpha-methyl-5-HT > ergotamine. 5-HT and 5-CT relaxations were reduced by the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulphonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride and potentiated by (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide dihydrochloride (WAY 100135) and cyanopindolol, 5-HT(1A) and 5-HT(1A/1B) receptor antagonists respectively. Inhibitors of 5-HT(1B/1D), 5-HT(2), 5-HT(2B/2C), 5-HT(3), 5-HT(4), 5-HT(5A) and 5-HT(6) receptors failed to modify 5-HT responses. Blockade of monoamine oxidase A/B, noradrenergic neurotransmission, alpha-adrenoceptors, muscarinic and purinergic receptors, nitric oxide synthase, guanylate cyclase and prostanoid synthesis did not alter relaxations to 5-HT. Inhibitors of Ca(2+)-activated K(+) and ATP-dependent K(+) channels failed to modify 5-HT responses but blockade of neuronal voltage-gated Na(+)-, Ca(2+)- and voltage-gated K(+) (K(v))-channels potentiated these relaxations. Adenylyl cyclase activation and cAMP-dependent protein kinase (PKA) inhibition potentiated and reduced, respectively, 5-HT-induced responses. Under non-adrenergic, non-cholinergic, non-nitrergic conditions, EFS induced neurogenic, frequency-dependent, relaxations which were resistant to WAY 100135 and cyanopindolol.
5-HT relaxed the pig urinary bladder neck through muscle 5-HT(7) receptors linked to the cAMP-PKA pathway. Prejunctional 5-HT(1A) receptors and K(v) channels modulated 5-HT-induced relaxations whereas postjunctional K(+) channels were not involved in such responses. 5-HT(7) receptor antagonists could be useful in the therapy of urinary incontinence produced by intrinsic sphincter deficiency.
5-羟色胺(5-HT)是膀胱出口区域的抑制性介质之一。在此,我们研究了5-HT诱导猪膀胱颈松弛的相关机制。
将去除尿路上皮的猪膀胱条安装在器官浴槽中,用于记录对5-HT和电场刺激(EFS)的等长力反应。
在去氧肾上腺素诱导收缩后,5-HT和5-HT受体激动剂使标本呈浓度依赖性松弛,效力顺序为:5-羧酰胺色胺(5-CT)>5-HT = RS67333>(±)-8-羟基-2-二丙基氨基四氢萘溴化物>间氯苯双胍>α-甲基-5-HT>麦角胺。5-HT和5-CT的松弛作用被5-HT(7)受体拮抗剂(2R)-1-[(3-羟基苯基)磺酰基]-2-[2-(4-甲基-1-哌啶基)乙基]吡咯烷盐酸盐减弱,而被(S)-N-叔丁基-3-(4-(2-甲氧基苯基)-哌嗪-1-基)-2-苯基丙酰胺二盐酸盐(WAY 100135)和氰吲哚洛尔分别增强,它们分别是5-HT(1A)和5-HT(1A/1B)受体拮抗剂。5-HT(1B/1D)、5-HT(2)、5-HT(2B/2C)、5-HT(3)、5-HT(4)、5-HT(5A)和5-HT(6)受体的抑制剂未能改变5-HT反应。单胺氧化酶A/B、去甲肾上腺素能神经传递、α-肾上腺素受体、毒蕈碱和嘌呤能受体、一氧化氮合酶、鸟苷酸环化酶和前列腺素合成的阻断均未改变对5-HT的松弛作用。钙激活钾通道和ATP依赖性钾通道的抑制剂未能改变5-HT反应,但神经元电压门控钠通道、钙通道和电压门控钾通道(K(v))的阻断增强了这些松弛作用。腺苷酸环化酶激活和cAMP依赖性蛋白激酶(PKA)抑制分别增强和减弱了5-HT诱导的反应。在非肾上腺素能、非胆碱能、非一氧化氮能条件下,EFS诱导神经源性、频率依赖性松弛,且对WAY 100135和氰吲哚洛尔有抗性。
5-HT通过与cAMP-PKA途径相关的肌肉5-HT(7)受体使猪膀胱颈松弛。突触前5-HT(1A)受体和K(v)通道调节5-HT诱导的松弛,而突触后钾通道不参与此类反应。5-HT(7)受体拮抗剂可能对治疗内在括约肌缺陷引起的尿失禁有用。