Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor.
Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites. In this study, we demonstrated the presence of three distinct 5-HT receptors localized at parasympathetic nerve terminals of the human bladder by measuring electrically evoked tritiated acetylcholine release in isolated detrusor strips. These prejunctional receptors, involved in both positive and negative feedback mechanisms regulating cholinergic transmission, have been characterized by means of three highly selective 5-HT antagonists for 5-HT(4), 5-HT(7), and 5-HT(1A) receptors, namely GR113808A ([1-[2-[(-methylsulphonyl) amino] ethyl]4-piperinidyl]methyl1-methyl-1H-indole-3-carboxylate succinate), SB269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol hydrochloride], and WAY100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexane-carboxamide trichloride]. Under these conditions, we confirmed the facilitatory role of 5-HT(4) heteroreceptors on acetylcholine release and revealed for the first time the occurrence of 5-HT(7) and 5-HT(1A) heteroreceptors with a facilitatory and an inhibitory action, respectively. Our findings strengthen the novel concept for the use of recently patented selective 5-HT agonists and antagonists for the control of OAB dysfunctions associated with inflammatory conditions, although their therapeutic efficacy needs to be explored in the clinical setting.
D'Agostino
Gianluigi
G
Department of Experimental and Applied Pharmacology, School of Pharmacy, University of Pavia, Viale Taramelli 14, I-27100 Pavia, Italy. dagg@unipv.it
Condino
Anna M
AM
Gallinari
Paola
P
Franceschetti
Gian P
GP
Tonini
Marcello
M
D000109:Acetylcholine / Q000378:metabolism*; D000368:Aged; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D000109:Acetylcholine