5-hydroxytryptamine induced relaxation in the pig urinary bladder neck

Abstract

Background and purpose: 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. Experimental approach: Urothellum-denuded strips of pig bladder were mounted in organ baths for isometric force recordings of responses to 5-HT and electrical field stimulation (EFS). Key results: 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 > (±)-8hydroxy-2-dipropyiamlnotetralinhydrobromlde > m-chlorophenylbiguanide > α-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-1piperidinyl)ethyl] pyrrolldine hydrochloride and potentiated by (S)-N-tert-butyl-3-(4-(2- methoxyphenyl)-piperazin-1-yl)-2phenylpropanamide dihydrochloride (WAY 100135) and cyanoplndolol, 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, a-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 voltagegated 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-adrenerglc, non-cholinergic, nonnitrerglc conditions, EFS induced neurogenic, frequency-dependent, relaxations which were resistant to WAY 100135 and cyanopindolol. Conclusions and implications: 5-HT relaxed the pig urinary bladder neck through muscle 5-HT. receptors linked to the cAMP-PKA pathway. Prejunctional 5-HTu receptors and K vchannels 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. © 2009 The British Pharmacological Society All rights reserved.