Enhancement of the intrinsic defecation reflex by mosapride, a 5-HT4 agonist, in chronically lumbosacral denervated guinea pigs

Abstract

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT4 receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT4 receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT4 receptors which may be post-synaptically located in the myenteric plexus of the anorectum.

A new possibility for repairing the anal dysfunction by promoting regeneration of the reflex pathways in the enteric nervous system

“…This indicates that 5-HT 4 -receptor activation can enhance intrinsic R-R and R-IAS reflexes that are functionally compromised after deprivation of extrinsic nerves and that this action is mediated through intrinsic pathways (9,10). Accordingly, following lower anterior resection, mosapride can enhance the reflexes after the regeneration of the nerve pathways.…”

“…These coordinated responses involve both extrinsic reflexes via autonomic nervous system and intrinsic reflexes via enteric nervous system (17, 19 -21, 26). The plasticity of these intrinsic reflex pathways has been shown in models involving chronic destruction of lumbar and sacral cords in guinea pig (9,10). After the lower anterior resection for rectal cancer, however, long-lasting defecation disturbances occur in many patients owing to the impairment of reflex pathways.…”

HPLC‐fluorescence assay for measuring mosapride in small volumes of rat plasma

“…Animal models such as rats (Aoki et al, 2007), guinea pigs (Kojima et al, 2006) and mice (Asakawa et al, 2006) are commonly used in the pharmacokinetic and pharmacological studies of mosapride to explore its clinical eff ects. To investigate these issues, a sensitive assay that requires small sample volume for measuring mosapride in small animals such as rats is necessary.…”

Mechanical and electrical responses modulated by excitation of inhibitory nerves during stimulation with high-potassium solutions in circular smooth muscle of the rabbit rectum

“…Rectal smooth muscle receives both sympathetic excitatory and inhibitory nerves in the cat (Hedlund et al, 1984;Carlstedt et al, 1988) and human (Carlstedt et al, 1988). An important role for NO as the transmitter of inhibitory nerves during relaxation of the rectum in response to hypogastric nerve excitation is suggested (O'Kelly et al, 1994;Kojima et al, 2006), and is supported by the rich distribution of NO-containing nerves in the myenteric layer of the rectum in human (O'Kelly et al, 1994;Seo et al, 1994). It is expected that smooth muscle tissue will produce complex responses during stimulation with high-K solutions, since this stimulation may depolarize both smooth muscle cells and the intramural nerves: the smooth muscle may contract due to the enhancement of Ca 2+ influx as a result of depolarization of the membrane, while depolarization of intramural nerves may release different types of transmitter substances and modulate smooth muscle activity.…”