Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators in response to immunoglobulin E and specific antigens. However, they are also triggered by neuropeptides, they have been found in close contact with neurons, and they are activated in diseases such as angioedema, interstitial cystitis and irritable bowel disease, the prevalence of which is much higher in women. When tested on purified rat peritoneal mast cells, 17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner, whether stimulated by the mast cell secretagogue compound 48/80 or the neuropeptide substance P. However, 17 beta-estradiol did not augment mast cell secretion stimulated by immunoglobulin E and specific antiserum indicating that immunologic stimulation is under different regulation. Testosterone inhibited secretion induced by compound 48/80. Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80. Moreover, tamoxifen antagonized the synergistic effect of phorbol myristate and the cation ionophore A23187 on mast cell secretion, suggesting that tamoxifen's inhibition may be due to regulation of protein kinase C activity. Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion.
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PMID:Estradiol augments while tamoxifen inhibits rat mast cell secretion. 138 69

To investigate the possibility of a neural deterioration of the bladder wall in interstitial cystitis, bladder tissue from 10 patients with interstitial cystitis was compared with that from 10 control subjects by means of immunohistochemistry. An enhanced innervation of the bladder in the submucosa and detrusor muscle was found to represent an increase of sympathetic but not cholinergic neurons. In interstitial cystitis the number of neurons positive for vasoactive intestinal polypeptide and neuropeptide Y was higher and carried a larger number of axonal varicosities, whereas the number of neurons positive for substance P and calcitonin-gene-related peptide was not significantly different in both groups. We conclude that interstitial cystitis is associated with increased sympathetic outflow into the bladder and altered metabolism of vasoactive intestinal polypeptide and neuropeptide Y. Since similar changes have been observed in other inflammatory diseases of a presumably autoimmune nature, such as rheumatoid arthritis, Crohn's disease and colitis ulcerosa, the pathophysiology of interstitial cystitis may share common pathways with the latter. Experience in these diseases may facilitate a better understanding of the pathophysiology of interstitial cystitis and suggest new therapeutic concepts.
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PMID:Interstitial cystitis: increased sympathetic innervation and related neuropeptide synthesis. 153 34

In order to examine the role of mast cells in the inflammatory bladder disease interstitial cystitis, mast cells isolated from the human bladder of normal and diseased tissue were challenged with a range of secretagogues. Calcium ionophore A23187 and anti-IgE caused histamine release from all bladder mast cells in a dose-related manner. Mast cells from the diseased tissue were far more responsive than those from the normal tissue. Mast cells from the muscle of normal bladder were responsive towards substance P and compound 48/80. However, mast cells from interstitial cystitis bladder did not release significant amounts of histamine with these two secretagogues.
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PMID:Does the mast cell have an intrinsic role in the pathogenesis of interstitial cystitis? 752 43

Many patients with interstitial cystitis (IC) also have irritable bowel syndrome (IBS), both of which occur overwhelmingly in women, are characterized by pain, and worsen under stress. Bladder and colon biopsies of a female patient with both IC and IBS were evaluated immunohistochemically. There were 40 +/- 10 mast cells (MC)/mm2 (normal, less than 10) in the bladder, which were degranulated. The colon contained 148 +/- 11 MC/mm2 (normal, less than 50), mostly close to numerous substance P (SP)-positive nerves. Histamine, methylhistamine, and the unique MC enzyme tryptase were evaluated in 24-hour urine during two flare-ups. These results may help explain the concurrent presentation and the painful nature of these syndromes.
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PMID:Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis. 863 18

In addition to transmitters stored in and released from terminals of efferent nerves, transmitters of afferent nerves and their receptors are also involved in the control of lower urinary tract function. Tachykinins, such as substance P and neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the the lower urinary tract and shown to be able to influence bladder function. Drugs affecting these nerves by causing release of tachykinins, and agents antagonizing tachykinin receptors, may be of therapeutic interest. New information on the alpha-adrenoceptor and muscarinic receptor subtypes mediating contraction of the human urethra and detrusor, respectively, has emerged, and may be the basis for the development of compounds with selectivity for the urethra or the bladder 'Non-classical' transmitters, such as nitric oxide, may also be of importance for bladder function. Nitric oxide derived from nerves seems to be involved in reflex relaxation of the outflow region at the start of micturition. However, nitric oxide derived from other sources may have a role in bladder disorders, such as interstitial cystitis.
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PMID:Neurotransmitters and neuroreceptors in the lower urinary tract. 894 35

Interstitial cystitis (IC) is a sterile bladder condition occurring primarily in females. It is characterized by frequency, nocturia, and suprapubic pain. IC symptoms are exacerbated during ovulation and under stress, thus implicating neurohormonal processes. The most prevalent theories to explain the pathophysiology of IC appear to be altered bladder lining and increased number of activated bladder mast cells. A defective bladder glycosaminoglycan (GAG) layer could allow penetration of allergic triggers, as well as chemicals, food preservatives, drugs, toxins, and adherent bacteria, all of which can activate bladder mast cells. Vasoactive, nociceptive, and proinflammatory molecules released can lead to immune cell infiltration and can sensitize neurons to secrete neurotransmitters or neuropeptides that can further activate mast cells. Mast cell-derived proteases can directly cause tissue damage, and it is noteworthy that urine tryptase is elevated in IC. Bladder mast cells are located close to neuronal processes, which are increased in IC, and they can be activated in situ by acetylcholine (ACh) and substance P (SP). Such activation is augmented by estradiol, which acquires significance in view of the fact that human bladder mast cells express estrogen receptors, but few progesterone receptors, which may explain the worsening of IC symptoms during ovulation. Finally, acute psychological stress in rats leads to mast cell activation that can be reduced by depletion of SP or neutralization of peripheral immune corticotropin-releasing hormone (CRH). These findings suggest that IC could be a syndrome with neural, immune, and endocrine components, in which activated mast cells play a central role.
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PMID:Interstitial cystitis: a neuroimmunoendocrine disorder. 962 89

1. We have developed and characterized a model of immediate hypersensitivity/inflammation of the urinary bladder in vivo induced by local application of ovalbumin (OA) in OA- sensitive female rats. Two parameters of the inflammatory response were assessed following OA challenge: plasma protein extravasation (PPE) and changes in smooth muscle reactivity. The former was estimated by measurement of Evans blue extravasation at 0.5, 2, 4, 8 and 24 h time point following in vivo challenge. Changes in reactivity were determined by measurement of isotonic tension responses of urinary bladder strips following OA challenge in vitro. 2. Acute in vivo intravesical OA challenge (10 mg in 0.3 ml saline) in actively sensitized female Wistar rats caused a time-dependent PPE in the urinary bladder which was biphasic with peak responses at 2-4 and 24 h. 3. The PPE response to acute OA challenge, above base-line, at 2 h was abolished by systemic capsaicin pretreatment (50 mg kg(-1), s.c., 4 days before use) (P < 0.05) whilst the response at 24 h was unaffected. The 2 h time point was then used for further studies. 4. Degranulation of mast cells, achieved by pretreatment with compound 48/80 (5 mg kg(-1), s.c. for 3 consecutive days), completely abolished the PPE response to OA challenge at the 2 h time point. 5. The tachykinin NK1 receptor antagonist, SR 140333 (0.1 micromol kg(-1), i.v.), abolished the 2 h PPE response whilst the tachykinin NK2 receptor antagonist MEN 11420 (0.1 micromol kg(-1), i.v.) appeared to reduce the response by approximately 50% but this did not reach significance. The bradykinin B2 receptor antagonist, Hoe 140 (0.1 micromol kg(-1), i.v.), similarly to SR 140333, blocked the 2 h PPE response to OA, whereas the selective B1 receptor antagonist B 9858 (0.1 micromol kg(-1), i.v.) had no significant effect. Inhibition of cyclo-oxygenase (COX) achieved by pretreatment with the COX inhibitor dexketoprofen (5.3 micromol kg(-1), i.v.) also blocked the PPE response, whilst the leukotriene receptor antagonist ONO 1078 (1 micromol kg(-1), i.v.) significantly reduced PPE by about 80%. 6. In the rat isolated urinary bladder OA (1 mg ml(-1)) challenge produced a biphasic response with a rapidly achieved maximal contraction followed by a sustained contraction for approximately 25 min. In vitro capsaicin pretreatment (10 microM for 15 min) significantly attenuated the duration of the sustained contraction whilst having no effect on the maximum contractile response achieved. In vivo pretreatment of animals with compound 48/80 significantly attenuated (42%) the maximum contractile response. Combination of both treatments almost completely abolished the response. In vitro treatment with Hoe 140 (1 microM) had no significant effect on the response to OA and neither did ONO 1078 (1 microM). 7. These results show that both the early inflammatory response and alterations in smooth muscle reactivity to OA challenge in actively sensitized animals are dependent on mast cell degranulation and the activation of sensory C-fibres. Furthermore this model of allergic cystitis may be useful for investigating both the processes involved and potential novel therapies in the treatment of interstitial cystitis.
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PMID:Ovalbumin-induced neurogenic inflammation in the bladder of sensitized rats. 963 Mar 59

Interstitial cystitis (IC) is a debilitating disease that has been adversely affecting the quality of women's lives for many years. The trigger in IC is not entirely known, and a role for the sensory nerves in its pathogenesis has been suggested. In addition to inflammation, increased mast cell numbers in the detrusor muscle have been reported in a subset of IC patients. Experimentally, several lines of evidence support a central role for substance P and neurokinin-1 (NK-1) receptors in cystitis. The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R(-/-)) allows us to directly evaluate the importance of substance P in cystitis. An unexpected finding of this investigation is that NK-1R(-/-) mice present increased numbers of mast cells in the bladder when compared with wild-type control mice. Despite the increase in mast cell numbers, no concomitant inflammation was observed. In addition, bladder instillation of wild-type mice with a sensitizing antigen induces activation of mast cells and an acute inflammatory response characterized by plasma extravasation, edema, and migration of neutrophils. Antigen-sensitized NK-1R(-/-) mice also exhibit bladder mast cell degranulation in response to antigen challenge. However, NK-1R(-/-) mice are protected from inflammation, failing to present bladder inflammatory cell infiltrate or edema in response to antigen challenge. This work presents the first evidence of participation of NK-1 receptors in cystitis and a mandatory participation of these receptors on the chain of events linking mast cell degranulation and inflammation.
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PMID:Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis. 1070 92

Interstitial cystitis (IC) represents a rare and complex inflammatory bladder condition in which diagnostics can be challenging. Strict NIH criteria for its diagnosis were designed for research purposes. Their routine application would miss large proportions of IC patients. When IC is suspected, history and physical exam are followed by an evaluation of long-term voiding diaries. Large voided volumes (functional capacity > 250 cc) or longer micturition intervals (> 2 h.), absence of nocturia or symptom-free periods reduce the likelihood of IC. Further exclusion diagnostics include urine tests (infection), cytology (in-situ carcinoma), ultrasound (calculi, bulks, anomalies) and urodynamics in selected cases. Bladder capacity measurements under sedoanalgesia are of limited value, since functional low-volume bladders can be mechanically extendable. Cystoscopy under general anesthesia represents the diagnostic standard procedure for IC during which 90% of IC-patients present with characteristic mucosal glomerulations after bladder distension. Biopsies are recommended for exclusion of malignancy. Potassium-leak testing plays no relevant role in routine diagnostics due to its poor sensitivity. Similarly, complex determinations of novel IC markers (histamine, tryptase, cytokines, growth factors, substance P, nitric oxide) are of no relevance in clinical settings and should be restricted to research projects.
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PMID:[Diagnosis of interstitial cystitis]. 1113 71

OBJECTIVES: To study the safety and efficacy of intravesically administered capsaicin, a C-fiber afferent neurotoxin, in patients with interstitial cystitis (IC). METHODS: A pilot study of intravesical capsaicin therapy was performed on 5 female patients diagnosed with IC using NIDDK criteria. Patients were evaluated with cystoscopy and CMG on initial presentation. Bladder capacity, urinary histamine, PGE2 and substance P were measured before and after treatment. A symptom score, visual analogue pain score and frequency/nocturia charts were completed before treatment and weekly thereafter by each patient. Topical anesthesia (30 mls of 0.5% bupivacaine) was instilled intravesically for 30 minutes prior to each treatment with capsaicin. The initial instillation consisted of vehicle (1% ethanol in normal saline) and subsequent weekly instillations of capsaicin in increasing concentrations (10, 50, 100, and 250 uM solutions in 1% ethanol) were given as tolerated by the patient. RESULTS: Four out of 5 of the patients experienced subjective improvement in both symptom and pain score. Bladder capacity improved in 1 patient and symptoms of frequency and nocturia improved in 2 patients. Urinary histamine and PGE2 revealed no trend between before and after treatment; however, 3 out of 5 of the patients did have a trend to decreased substance P. No complications were noted during the course of this study. CONCLUSIONS: Intravesical capsaicin is a safe and promising treatment for interstitial cystitis. A potential mechanism of action is desensitization of bladder C-fiber afferents which presumably initiate painful sensations in IC patients. Low dose intravesical capsaicin therapy represents a potential treatment option for interstitial cystitis.
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PMID:Intravesical capsaicin for the treatment of interstitial cystitis: a pilot study. 1117 98


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