Characterization of Prejunctional Serotonin Receptors Modulating [³H]Acetylcholine Release in the Human Detrusor

Abstract

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,. 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.

Dual Excitatory and Inhibitory Serotonergic Inputs Modulate Egg Laying inCaenorhabditis elegans

“…Recently, multiple serotonergic inputs regulating bladder contraction have been suggested on the basis of pharmacological analyses. For example, acetylcholine release from isolated detrusor muscle strips appears to be stimulated by Ga s -coupled 5-HT 4 and 5-HT 7 receptors and inhibited by Ga i/o -coupled 5-HT 1 receptors (D'Agostino et al 2006). Similarly, low concentrations of 5-HT (1 nm) inhibit and higher concentrations stimulate heart rate in Drosophila larvae, suggesting differential inputs from 5-HT receptors with potentially different affinities for 5-HT (Dasari and Cooper 2006).…”

The influence of doxazosin on the contractility of the urinary bladder in female pigs with experimentally induced cystitis

“…Functional 5-HT 7 receptors involved in facilitation of ACh release were found at parasympathetic nerve terminals in the isolated human urinary bladder (D'Agostino et al 2006). Activation of 5-HT 4 receptor subtype has been suggested to facilitate cholinergic transmission in the human and porcine detrusor muscle (Corsi et al 1991, Candura et al 1996, Sellers et al 2000.…”

Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

“…In HBSM, contractions are caused by the direct stimulation of 5-HT 2 receptors and by the activation of 5-HT 3 on the excitatory neurons [24]. In pig and human detrusor, the activation of 5-HT 4 potentiated the neurogenic contractions [20,23].…”

“…In pig and human detrusor, the activation of 5-HT 4 potentiated the neurogenic contractions [20,23]. Conversely, 5-HT 1A inhibitory heteroreceptors on cholinergic terminals might contribute to the increase in bladder capacity by reducing cholinergic neurotransmission [24].…”