1 We investigated muscarinic receptors in the detrusor and mucosa of the human bladder body. Radioligand-binding studies with [ 5 The presence of a high density of mainly M 2 muscarinic receptors in the mucosa appears to be a novel finding and raises the question of their physiological significance and the source of their endogenous ligand. 6 There was a negative correlation of receptor number (B max ) with age in detrusor muscle from male patients (P ¼ 0.02). Quantitative competitive RT-PCR demonstrated a selective age-related decrease in mRNA for muscarinic M 3 but not M 2 receptors, in both male (Po0.0001) and female (P ¼ 0.019) detrusor. These findings correspond with reports of decreased detrusor contractility with ageing.
The role of NK1 and NK3 receptors in synaptic transmission between myenteric neurons during motility reflexes in the guinea‐pig ileum was investigated by recording intracellularly the reflex responses of the circular muscle to distension or compression of the mucosal villi. Experiments were performed in a three‐chambered organ bath that enabled drugs to be selectively applied to different sites along the reflex pathways. When applied in the recording chamber, an NK1 receptor antagonist, SR140333 (100 nm), reduced by 40–50% the amplitudes of inhibitory junction potentials (i.j.ps) evoked in the circular muscle by activation of descending reflex pathways. This effect was abolished when synaptic transmission in the stimulus region was blocked with physiological saline containing 0.1 mm Ca2+ plus 10 mm Mg2+, leaving only the component of the descending reflex pathway conducted via long anally directed collaterals of intrinsic sensory neurons. SR140333 (100 nm) had no effect on descending reflex i.j.ps when applied to the stimulus region. Ascending reflexes were also unaffected by SR140333 in the stimulus region or between the stimulus and recording sites. Septide (10 nm), an NK1 receptor agonist, enhanced descending reflexes by 30–60% when in the recording chamber. [Sar9,Met(O2)11]substance P had no effect at 10 nm, but potentiated distension‐evoked reflexes at 100 nm. A selective NK3 receptor antagonist, SR142801 (100 nm), when applied to the stimulus region, reduced the amplitude of descending reflex responses to compression by 40%, but had no effect on responses to distension. SR142801 (100 nm) had no effect when applied to other regions of the descending reflex pathways. SR142801 (100 nm) only inhibited ascending reflexes when applied at the recording site. However, after nicotinic transmission in the stimulus region was blocked, SR142801 (100 nm) at this site reduced responses to compression. Contractions of the circular muscle of isolated rings of ileum evoked by low concentrations of septide, but not [Sar9,Met(O2)11]substance P, were potentiated by tetrodotoxin (300 nm). Contractile responses evoked by an NK3 receptor agonist, senktide, were non‐competitively inhibited by SR142801. After excitatory neuromuscular transmission was blocked, senktide produced inhibitory responses that were also antagonised by SR142801, but to a lesser extent and in an apparently competitive manner. These results indicate that tachykinins acting via NK1 receptors partly mediate transmission to inhibitory motor neurons. NK3 receptors play a role in transmission from intrinsic sensory neurons and from ascending interneurons to excitatory motor neurons during motility reflexes. British Journal of Pharmacology (1998) 124, 1375–1384; doi:
The last decade has witnessed major breakthroughs in the study of tachykinin receptors. The currently described NK-1, NK-2, and NK-3 receptors have been sequenced and cloned from various mammalian sources. A far greater variety of tachykinin analogues are now available for use as selective agonists and antagonists. Importantly, potent nonpeptide antagonists highly selective for the NK-1 and NK-2 receptors have been developed recently. These improved tools for tachykinin receptor characterization have enabled us to describe at least three distinct receptor types. Furthermore, novel antagonists have yielded radioligand binding and functional data strongly favoring the existence of putative subtypes of NK-1 and especially NK-2 receptors. Whether these subtypes are species variants or true within-species subtypes awaits further evidence. As yet undiscovered mammalian tachykinins, or bioactive fragments, may have superior potency at a specific receptor class. The common C terminus of tachykinins permits varying degrees of interaction at essentially all tachykinin receptors. Although the exact physiological significance of this inherent capacity for receptor "cross talk" remains unknown, one implication is for multiple endogenous ligands at a single receptor. For example, NP gamma and NPK appear to be the preferred agonists and binding competitors at some NK-2 receptors, previously thought of as exclusively "NKA-preferring." Current evidence suggests that tachykinin coexistence and expression of multiple receptors may also occur with postulated NK-2 and NK-1 receptor subtypes. Other "tachykinin" receptors may recognize preprotachykinins and the N terminus of SP. In light of these recent developments, the convenient working hypothesis of three endogenous ligands (SP, NKA, and NKB) for three basic receptor types (NK-1, NK-2, and NK-3) may be too simplistic and in need of amendment as future developments occur (Burcher et al., 1991b). In retrospect, the 1980s contributed greatly to our understanding of the structure, function, and regulation of tachykinins and their various receptors. The development of improved, receptor subtype-selective antagonists and radioligands, in addition to recent advances in molecular biological techniques, may lead to a more conclusive pharmacological and biochemical characterization of tachykinin receptors. The 1990s may prove to be the decade of application, where a better understanding of the roles played by endogenous tachykinins (at various receptor subtypes) under pathophysiological conditions will no doubt hasten the realization of clinically useful therapeutic agents.
Background and purpose: ATP, released from urothelial cells, modulates afferent nerve firing from the urinary bladder. Here, we have characterized ATP release from the rat bladder mucosa in response to acid, capsaicin, electrical field stimulation (EFS) and stretch, using agonists and antagonists at transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs). Experimental approach: Rat mucosal strips (containing urothelium and lamina propria) in Perspex microbaths were superfused with Krebs solution. ATP was measured after exposure of matched strips to acid (pH 6.6-5.0), capsaicin (0.1-10 mM), EFS or stretch (150% of original length). Key results: Median basal ATP release was 3.46 nmol·g . ATP release in response to acid was pH dependent (P < 0.05). Responses to capsaicin did not desensitize nor were they concentration dependent. TRPV1 antagonist, capsazepine (10 mM) abolished capsaicin-evoked ATP release, and reduced acid-evoked (pH 6.5) release to 30% (P < 0.001). The ASIC channel antagonists gadolinium (0.1 mM) and amiloride (0.3 mM) reduced (P < 0.05) the acid-evoked (pH 6.5) release to 40 and 6.5% respectively. ASIC (ASIC1, ASIC2a, ASIC2b, ASIC3) and two TRPV1 gene products were detected in mucosal and detrusor extracts. Conclusions and implications: Capsaicin (at TRPV1) and acid (at both TRPV1 and ASIC) induce ATP release from the rat bladder mucosa. This ATP appears to be principally of urothelial origin. This study highlights the importance of ATP and acid as signalling molecules in modulating bladder function.
The tachykinins are a family of peptides with the carboxyl terminal amino acid sequence Phe-X-Gly-Leu-Met-NH2. Three major mammalian tachykinins have been identified--substance K, neuromedin K, and substance P--but only two tachykinin receptors have been postulated. Three tachykinins were labeled with radioiodinated Bolton-Hunter reagent and their binding characteristics were determined in crude membrane suspensions from several tissues. In cerebral cortex labeled eledoisin exhibited high-affinity binding that was inhibited by tachykinins in a manner indicating a definitive SP-E receptor site. In gastrointestinal smooth muscle and bladder, high-affinity binding of labeled substance P was inhibited in a pattern indicating a definitive SP-P site. In intestinal smooth muscle and bladder, however, labeled substance K and labeled eledoisin were both bound in a pattern indicating a preference for substance K itself. The results suggest the existence of three distinct types of tachykinin receptors: SP-P, SP-E, and SP-K.
Background and purpose: The bladder urothelium is now known to have active properties. Our aim was to investigate the contractile properties of the urinary mucosa in response to the tachykinin neurokinin A (NKA) and carbachol. Experimental approach: Discrete concentration-response curves for carbachol and NKA were obtained in matched strips of porcine detrusor, mucosa and intact bladder, suspended in organ baths. The effects of inhibitors and tachykinin receptor antagonists were studied on NKA-mediated contractions in mucosal strips. Intact sections of bladder and experimental strips were processed for histology and immunohistochemistry. Key results: All types of strips contracted to both carbachol and NKA. Mucosal responses to NKA (pD 2 7.2) were higher than those in intact strips and were inhibited by the NK 2 receptor antagonist SR48968 (pK B 9.85) but not the NK 1 receptor antagonist SR140333, tetrodotoxin or indomethacin. Immunostaining for smooth muscle actin and vimentin occurred under the urothelium and on blood vessels. Desmin immunostaining and histological studies showed only sparse smooth muscle to be present in the mucosal strips. Removal of smooth muscle remnants from mucosal strips did not alter the responses to NKA. Conclusions and implications:This study has shown both functional and histological evidence for contractile properties of the mucosa, distinct from the detrusor. Mucosal contractions to NKA appear to be directly mediated via NK 2 receptors. The main cell type mediating mucosal contractions is suggested to be suburothelial myofibroblasts. Mucosal contractions may be important in vivo for matching the luminal surface area to bladder volume.
The symptoms of SU were associated with the increased expression of TRPV1 mRNA in the trigonal mucosa. No upregulation or regional differences of TRPV1 mRNA were seen in IDO patients. TRPV1 may play a role in SU and premature first bladder sensation on filling.
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