Urothelium‐derived inhibitory factor(s) influences on detrusor muscle contractility in vitro

Abstract

The function of the bladder urothelium in modulating contractile responses of the underlying detrusor smooth muscle to muscarinic stimulation has been examined in the pig bladder. Saturation curves for [ 3 H]-QNB binding demonstrated a greater muscarinic receptor density in the urothelium than in the detrusor smooth muscle. The presence of an intact urothelium on isolated bladder strips inhibited contractions induced by carbachol but not KCl. Contractions of a urothelium-denuded muscle strip were inhibited in the presence of a second bladder strip with an intact urothelium, but not if the second strip was denuded. The urothelium-induced inhibition of contractions was not prevented in the presence of L-NOARG, methylene blue, indomethacin, propranolol, suramin, TEA or apamin. The data suggest the presence of a diusable, urothelium-derived inhibitory factor, which could not be identi®ed but appears to be neither nitric oxide, a cyclo-oxygenase product, a catecholamine, adenosine, GABA nor an EDHF sensitive to apamin.

M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

“…Our determination of receptor density closely matches data from receptor binding protocols [Hawthorn et al, 2000;Mans¢eld et al, 2005], with a greater density in the urothelium than in the smooth muscle for pig bladders. The immunoprecipitated M 2 and M 3 receptors accounted for 69% of the total urothelial and 61% of the total muscle receptors.…”

“…This alludes to a role of bladder urothelium in causing the change in phenotype of detrusor smooth muscle from the M 3 contractile phenotype to either mixed M 2 and M 3 phenotype or the M 2 contractile phenotype, due to the increased density of muscarinic receptors in the urothelium. Inhibition of smooth muscle contraction is induced by functional urothelium, suggesting the presence of a di¡usible inhibitory factor [Hawthorn et al, 2000]. This di¡usible inhibitory factor has yet to be identi¢ed, however, studies in pig and human but not rat bladder strips have suggested that carbachol stimulation of muscarinic urothelial receptors leads to the release of this di¡usible inhibitory factor which can regulate detrusor contractility [Hawthorn et al, 2000;Chess-Williams, 2002;Chaiyaprasithi et al, 2003].…”

“…Inhibition of smooth muscle contraction is induced by functional urothelium, suggesting the presence of a di¡usible inhibitory factor [Hawthorn et al, 2000]. This di¡usible inhibitory factor has yet to be identi¢ed, however, studies in pig and human but not rat bladder strips have suggested that carbachol stimulation of muscarinic urothelial receptors leads to the release of this di¡usible inhibitory factor which can regulate detrusor contractility [Hawthorn et al, 2000;Chess-Williams, 2002;Chaiyaprasithi et al, 2003]. Similarly, it is possible that a urothelial derived di¡usable factor determines the phenotype of the detrusor contraction.…”

“…M 1 , M 2 , M 3 , and M 5 have been detected, with a minor M 1 population, and an M 2 to M 3 and/or M 5 ratio of 3:1 in radioligand binding studies [Mans¢eld et al, 2005].The relationship of urothelial activity and its e¡ect on muscle contraction has been investigated. Possible urothelial factors such as nitric oxide, guanylate cyclase, cyclo-oxygenase, P2Y receptors, catecholamines, GABA, and endothelium-derived hyperpolarizing factor (EDHF) do not mediate the inhibitory function of the pig urothelium [Hawthorn et al, 2000]. Although the mechanism remains unclear, there is a known inhibitory function of the urothelium on smooth muscle after urothelial activation in the human bladder [Chaiyaprasithi et al, 2003].…”

Urothelial/Lamina Propria Spontaneous Activity and the Role of M3 Muscarinic Receptors in Mediating Rate Responses to Stretch and Carbachol

“…Local mechanisms appear to be involved since spontaneous contractile activity of isolated tissues has been observed (Jiang et al, 2005). In recent years the urothelium and the underlying lamina propria (here abbreviated to U&LP) have been recognized as important regulators of bladder activity, releasing factors that modulate detrusor contraction (Hawthorn et al, 2000, Templeman et al, 2002 and sensory nerve activity (Cockayne et al, 2000). Furthermore, these roles may be clinically relevant since the inhibitory effect these tissues have on detrusor contraction is depressed in the neurogenic overactive bladder (Chess-Williams, 2009), while non-neuronal ATP release from this tissue is enhanced in the bladders of patients with painful bladder (sensory) syndrome (Kumar et al, 2007).…”