5-hydroxytryptamine induced relaxation in the pig urinary bladder neck.
OBJECTIVE
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.


METHODS
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).


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 > (+/-)-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.


CONCLUSIONS
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.
Recio
Paz
P
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Barahona
María Victoria
MV
Orensanz
Luis M
LM
Bustamante
Salvador
S
Martínez
Ana Cristina
AC
Benedito
Sara
S
García-Sacristán
Albino
A
Prieto
Dolores
D
Hernández
Medardo
M
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology
D015221:Potassium Channels; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D017868:Cyclic AMP-Dependent Protein Kinases