Abstract:Our aim was to investigate whether guinea pig urothelium-derived bioactivities compatible with the existence of urothelium-derived inhibitory factor could be demonstrated by in vitro serial bioassay and whether purinergic P1 receptor agonists, nitric oxide, nitrite or prostaglandins might explain observed activities. In a cascade superfusion system, urothelium-denuded guinea pig ureters were used as bioassay tissues, recording their spontaneous rhythmic contractions in presence of scopolamine. Urothelium-intac… Show more
“…Hawthorn et al reported smaller carbachol‐evoked contractions in intact strips of pig bladder compared with mucosa‐free strips; moreover, mucosa‐free strip contractions were inhibited by the presence of a second intact strip indicating release of a modulatory signal. The exact identity of this diffusible UDIF is not yet known although several candidates have been proposed and excluded …”
Section: Introductionmentioning
confidence: 99%
“…The exact identity of this diffusible UDIF is not yet known although several candidates have been proposed and excluded. 8 Botulinum toxin type A (BoNT-A) is used to treat antimuscarinic refractory detrusor overactivity (DO) where involuntary detrusor contractions can be observed and overactive bladder syndrome (OAB) where DO may or may not be demonstrable. 9 The established mechanism of action of BoNT-A on neurones involves cleavage of synaptosome-associated protein-25 (SNAP-25), a component of the neuronal SNARE complex, preventing neuronal transmitter release.…”
The mucosal layer positively modulates spontaneous contractions in strips from normal SD but not overactive SHR bladder strips. The novel finding of BoNT-A reduction of contractions in SHR mucosa-free strips indicates actions on the detrusor, independent of its classical action on neuronal SNARE complexes.
“…Hawthorn et al reported smaller carbachol‐evoked contractions in intact strips of pig bladder compared with mucosa‐free strips; moreover, mucosa‐free strip contractions were inhibited by the presence of a second intact strip indicating release of a modulatory signal. The exact identity of this diffusible UDIF is not yet known although several candidates have been proposed and excluded …”
Section: Introductionmentioning
confidence: 99%
“…The exact identity of this diffusible UDIF is not yet known although several candidates have been proposed and excluded. 8 Botulinum toxin type A (BoNT-A) is used to treat antimuscarinic refractory detrusor overactivity (DO) where involuntary detrusor contractions can be observed and overactive bladder syndrome (OAB) where DO may or may not be demonstrable. 9 The established mechanism of action of BoNT-A on neurones involves cleavage of synaptosome-associated protein-25 (SNAP-25), a component of the neuronal SNARE complex, preventing neuronal transmitter release.…”
The mucosal layer positively modulates spontaneous contractions in strips from normal SD but not overactive SHR bladder strips. The novel finding of BoNT-A reduction of contractions in SHR mucosa-free strips indicates actions on the detrusor, independent of its classical action on neuronal SNARE complexes.
“…There was also a tendency to higher force development in response to carbachol, but this difference did not reach statistical significance. These results suggest that endogenous NO may attenuate the level of stimulated tension development [3] and confirm that NO is probably not the urothelium-derived relaxing factor [4,25,26]. Moreover, NO is unlikely to be involved in noradrenaline-induced relaxation because L-NAME had no effect on the concentration-relaxation curves with or without urothelium.…”
Objectives: The mucosa of human detrusor strips impairs catecholamine-induced relaxation. In order to elucidate which signal transduction pathways are involved in this cross talk between the mucosa and detrusor, we have studied the effects of several pharmacological agonists and antagonists on noradrenaline-mediated relaxation in intact and mucosa-denuded detrusor strips. Patients and Methods: Strips of detrusor tissue were obtained from patients who had undergone cystectomy for bladder cancer and were set up for force measurement. KCl- or carbachol-precontracted strips were relaxed with increasing concentrations of noradrenaline in the absence and in the presence of nitric oxide synthase inhibitor, L-NAME; P2X-receptor antagonist, PPADS; ETA-receptor antagonist, BQ-123; ETB-receptor antagonist, BQ-788; cyclooxygenase inhibitor, diclofenac; AT1-receptor antagonist, candesartan; and NK1-receptor antagonist, L-703,606. Results: In intact strips, KCl-stimulated force was enhanced by all blockers; carbachol-stimulated force increased with L-703,606. In denuded strips, only L-NAME augmented the KCl-stimulated contraction. Noradrenaline relaxed the precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. L-NAME, PPADS and BQ-123/BQ-788 had little effect on noradrenaline-induced relaxation, whereas diclofenac, candesartan and L-703,606 sensitized intact carbachol-stimulated detrusor strips to noradrenaline-induced relaxation. Conclusion: Inhibition of the noradrenaline-induced relaxation of precontracted human detrusor strips by the mucosa is attenuated by diclofenac, candesartan and L-703,606 suggesting the involvement of prostanoids, angiotensin and neurokinin pathways. Further experiments are required to unravel the exact mechanisms.
“…The study using human bladder strips showed that the factor was distinct from nitric oxide and it persisted in the presence of beta‐adrenoceptor blockade or cyclooxygenase inhibition. The existence of the urothelium‐derived inhibitory factor in the guinea pig urinary bladder was also demonstrated by assay on the spontaneous contracted guinea pig ureters in a cascade superfusion bioassay system, which offers further possibilities to identify the factor . The results indicated a transmissible inhibitory factor over a significant distance and seemed less likely to be nitric oxide, nitrite, an adenosine receptor agonist or cyclooxygenase products.…”
Section: Urothelium Released Unknown Inhibitory Factor(s)mentioning
The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium-derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor and cyclooxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD was found to have an inhibitory influence on nerve-induced contractions in guinea pig urinary bladder and on spontaneous contractions in the out-flow region. An altered release of excitatory and inhibitory factors is likely to play an important part in bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders.
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