Influence of urothelial or suburothelial cholinergic receptors on bladder reflexes in chronic spinal cord injured cats

Abstract

The effects of intravesical administration of a muscarinic receptor agonist (oxotremorine-M, OXO-M) and antagonist (atropine methyl nitrate, AMN) and of a nicotinic receptor agonist (nicotine) and antagonist (hexamethonium, C6) on reflex bladder activity were investigated in conscious female chronic spinal cord injured (SCI) cats using cystometry. OXO-M (50 μM) decreased bladder capacity (BC) for triggering micturition contractions, increased maximal micturition pressure (MMP), increased frequency and area under the curve of pre-micturition contractions (PMC-AUC). Nicotine (250 μM) decreased BC, increased MMP, but did not alter PMC-AUC. The effects of OXO-M on BC and PMC-AUC were suppressed by intravesical administration of AMN (50–100 μM), and the effects of nicotine were blocked by hexamethonium (1 mM). Antagonists infused intravesically alone did not alter reflex bladder activity. However, AMN (0.2 mg/kg, subcutaneously) decreased PMC-AUC. 8-OHDPAT (0.5 mg/kg, s.c.), a 5-HT1A receptor agonist, suppressed the OXO-M-induced decrease in BC but not the enhancement of PMC-AUC. These results indicate that activation of cholinergic receptors located near the lumenal surface of the bladder modulates two types of reflex bladder activity (i.e., micturition and pre-micturition contractions). The effects may be mediated by activation of receptors on suburothelial afferent nerves or receptors on urothelial cells which release transmitters that can in turn alter afferent excitability. The selective action of nicotine on BC, while OXO-M affects both BC and PMC-AUC, suggests that micturition reflexes and PMCs are activated by different populations of afferent nerves. The selective suppression of the OXO-M effect on BC by 8-OH-DPAT without altering the effect on PMCs supports this hypothesis. The failure of intravesical administration of either AMN or hexamethonium alone to alter bladder activity indicates that cholinergic receptors located near the lumenal surface do not tonically regulate bladder reflex mechanisms in the SCI cat.

Moxibustion attenuates neurogenic detrusor overactivity in spinal cord injury rats by inhibiting M2/ATP/P2X3 pathway

“…Normal urination depends on the activation of Aδ-ber bladder afferents, whereas C-ber afferent activation is generally considered to be associated with lower urinary tract dysfunction [40]. The neurotoxicity of capsaicin could prevent the occurrence of NDO in SCI cats, but had no effect on the micturition re ex of normal animals, further suggesting that the C-bers is not the main afferent ber in the normal micturition, but participates in the abnormal voiding contraction [10,41,42]. In this study, we also observed that a signi cant enhancement in the excitability of pelvic afferent nerve in rats with SCI and an obviously decrease following moxibustion treatment.…”

Injecting RNA interference lentiviruses targeting the muscarinic 3 receptor gene into the bladder wall inhibits neurogenic detrusor overactivity in rats with spinal cord injury

“…However, the high incidence of side effects greatly limits the use of these drugs . What's more, previous studies have suggested that intravesical administration of a non‐selective muscarinic receptor antagonist alone cannot affect bladder activity or cystometric parameters . In addition, cystometric parameters except time to first NVC were also not changed if oxybutynin chloride (a nonselective muscarinic receptor antagonist) was administered by oral gavage .…”

“…36 What's more, previous studies have suggested that intravesical administration of a non-selective muscarinic receptor antagonist alone cannot affect bladder activity or cystometric parameters. 10,17 In addition, cystometric parameters except time to first NVC were also not changed if oxybutynin chloride (a nonselective muscarinic receptor antagonist) was administered by oral gavage. 14 Not surprisingly, neither M 2 -selective nor M 3selective antagonists administered intravesically could affect cystometric parameters.…”

“…Moreover, the urothelial or suburothelial M 3 receptor was observed to be implicated in the interactions between urothelium and afferent nerves . Activation of M 3 receptor on suburothelial afferent nerves or receptor on urothelial cells could release various factors, such as adenosine triphosphate (ATP) and Ach, which interact with adjacent afferent nerves and modulate bladder afferent firing in turn . For example, the M 3 receptor has been shown to be involved in the release of ATP from the urothelium or urothelial cells cultured in vitro …”

“…8 Activation of M 3 receptor on suburothelial afferent nerves or receptor on urothelial cells could release various factors, such as adenosine triphosphate (ATP) and Ach, which interact with adjacent afferent nerves and modulate bladder afferent firing in turn. [9][10][11] For example, the M 3 receptor has been shown to be involved in the release of ATP from the urothelium or urothelial cells cultured in vitro. 12,13 As the mainstream treatment for overactive bladder (OAB) symptoms, antimuscarinic agents have been extensively studied in the area of neurogenic bladder dysfunction and been established as the first-line treatment for NDO.…”