Hydroxyzine inhibits neurogenic bladder mast cell activation.

OBJECTIVES: Increased numbers of activated mast cells have been documented close to substance P (SP) containing nerve endings in the bladders of patients with interstitial cystitis (IC), a painful, sterile bladder disorder occurring primarily in females. Many of these patients also suffer from allergies, but common antihistamines do not help. In line with the fact that IC symptoms worsen under stress, we recently showed that bladder mast cells could be activated by the stable acetylcholine (Ach) analogue carbachol and by immobilization stress. Preliminary data from open label studies indicated that the heterocyclic histamine-1 receptor antagonist (H-1r alpha) hydroxyzine reduces IC symptoms. We, therefore, investigated whether hydroxyzine could inhibit carbachol-induced bladder mast cell activation. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with 10(-5) M carbachol, 10(-5) M SP, or 100 microg/ml compound 48/80 (C48/80), with or without preincubation with the designated concentrations of the H-1r alpha. Mast cell activation was assessed by release of exogenous 3H-serotonin and morphological evidence of secretion by light microscopy. RESULTS: Carbachol at 10(-5) M triggered rat bladder mast cell serotonin release which represented a 65% increase over control. Equimolar concentrations of SP caused a 32% increase, while C48/80 had no effect. The heterocyclic piperazine H-1r alpha hydroxyzine reduced carbachol-induced serotonin release by 25% at 10(-6) M and 34% at 10(-5) M, both of which were statistically significant (P < 0.05). On the contrary, the well known H-1r alpha diphenhydramine had no inhibitory effect, while the mixed H-1r alpha and 5-hydroxytryptamine-receptor antagonist (5-HTr alpha) azatadine actually caused an 11% increase. CONCLUSION: Hydroxyzine reduced carbachol-induced serotonin release from rat bladder in vitro through a mechanism which was unrelated to its H-1 receptor antagonistic properties. The ability of hydroxyzine to inhibit bladder mast cell activation by neurogenic stimuli along with its anticholinergic, anxiolytic and analgesic properties, may explain the clinical efficacy of this drug in reducing IC symptoms. Other, nonsedating, hydroxyzine analogues able to inhibit bladder mast cell activation may provide potentially new therapeutic approaches for IC.

Carbachol-induced bladder mast cell activation: augmentation by estradiol and implications for interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) is a painful, sterile bladder disorder that occurs primarily in women, many of whom also experience allergies with symptoms that worsen perimenstrually. Increased numbers of activated bladder mast cells have recently been implicated in the pathophysiology of IC. These mast cells express high-affinity estrogen receptors and are located close to increased bladder nerves, many of which contain the neuropeptide substance P (SP). We therefore investigated whether the neurotransmitter acetylcholine (ACh) and SP could activate bladder mast cells and whether estradiol could influence this effect. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with carbachol (the stable analogue of ACh), SP, or the mast cell secretagogue compound 48/80 (C48/80) with or without preincubation with beta-estradiol. The effect of carbachol was also investigated after pretreatment with the muscarinic antagonist atropine. Mast cell activation was assessed by release of 3H-serotonin and morphologic evidence of secretion by light and electron microscopy. RESULTS: Carbachol triggered rat bladder mast cell serotonin release in a dose-dependent manner, an effect increased by tissue pretreatment with estradiol and blocked by atropine. The effect of carbachol was accompanied by ultrastructural evidence of mast cell activation and was stronger than that obtained by either C48/ 80 or SP. CONCLUSIONS: Bladder mast cell activation is neurogenically mediated and augmented by estradiol, findings that could possibly explain the painful symptoms of IC and its prevalence in women, as well as the worsening of symptoms perimenstrually.

Elevated mast cell tryptase in the urine of patients with interstitial cystitis.

OBJECTIVE: To investigate the number of tryptase positive bladder mast cells and the level of urine tryptase in interstitial cystitis (IC), a bladder disorder which occurs mostly in women and is characterized by suprapubic pain, frequency and nocturia. PATIENTS AND METHODS: Bladder biopsies from 37 women with IC and 15 control women with other bladder conditions (age range 18-63 years) were obtained during diagnostic bladder distension and frozen immediately. Mast cells positive for tryptase were identified by immunohistochemistry and evaluated by light microscopy. Tryptase was measured by solid phase radioimmunoassay in urine samples, collected immediately (spot) and during a period of 24 h, obtained from normal women volunteers, controls and patients with IC. To adequately quantify tryptase, the physiologically active tetramer was dissociated to inactive monomers with supersaturated NaCl (6.0 M), and then dialysed. RESULTS: The patients' spot urine sample tryptase levels were indistinguishable from those of controls, which included the normal women volunteers. However, the tryptase levels in 24 h urine samples were greatly elevated only in patients with IC, both before (P < 0.005), and especially after NaCl treatment and dialysis (P < 0.001). CONCLUSION: These results indicate that the tryptase levels of 24 h urine samples, combined with methylhistamine levels and the clinical criteria presently used, may possibly help to better identify IC.

Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study.

Interstitial cystitis, a sterile bladder condition, is characterized by urinary frequency, urgency, burning and suprapubic pain. Increasing evidence indicates that interstitial cystitis is a heterogeneous syndrome that reflects an immune response to a variety of triggers. More than 50% of the patients have allergies, 30% have the irritable bowel syndrome and almost 20% suffer from migraine headaches. Increased numbers of mast cells have been reported in interstitial cystitis. Mast cell activation, which is critical if these cells were to be implicated in this syndrome, has been investigated by electron microscopy, which definitively shows mast cell secretion. Recently, methylhistamine, the major metabolite of histamine, and the specific mast cell marker, tryptase, were shown to be significantly elevated in urine of interstitial cystitis patients. Bladder biopsies from 53 patients were analyzed blindly for the number and degree of activation of mast cells using 4 different stains for light microscopy, as well as electron microscopy. Controls included 16 patients with incontinence and chronic bacterial cystitis. Mast cells in controls were less than 10/mm.2 and were all nearly intact. Surprisingly, mast cells from 11 cancer patients averaged 50/mm.2 but almost all were intact. In contrast, mast cells from 26 interstitial cystitis patients averaged 40/mm.2 and more than 90% were activated to various degrees. Therefore, bladder mast cell activation is a characteristic pathological finding in at least a subset of patients with interstitial cystitis.

Increased urine histamine and methylhistamine in interstitial cystitis.

Interstitial cystitis is a painful bladder disorder occurring mostly in women, and is presently diagnosed by clinical presentation, as well as the presence of mucosal glomerulations and inflammation on bladder distention. An increased number of bladder mast cells have been implicated in the pathophysiology of interstitial cystitis but previous reports of spot urine histamine have not confirmed bladder mast cell activation. The availability of easily measurable objective criteria could make the diagnosis easier. Histamine and its major metabolite, methylhistamine, were measured in spot and 24-hour urine specimens from a number of normal female volunteers, control patients and interstitial cystitis patients. In interstitial cystitis patients the histamine levels were only slightly increased in the spot (p < 0.01) and 24-hour urine (p < 0.03) collections. Methylhistamine, on the other hand, was greatly elevated in spot (p < 10(-10)) and 24-hour (p < 0.0008) urine samples. These results indicate that methylhistamine levels could serve as useful diagnostic end points for interstitial cystitis.

Dermatitis characterized by mastocytosis at immunization sites in mast-cell-deficient W/Wv mice.

W/Wv mice have been extensively used as an important model to study the maturation/differentiation and pathophysiology of mast cells. These albino mice have been shown to have less than 1% of the mast cells found in the skin of their +/+ controls or other normal mice. Moreover, no mast cells are detected in other organs even though they apparently have an adequate number of mast cell precursors. Presumably, these precursors do not respond appropriately to microenvironmental growth factors, while 'normal' precursors from the +/+ controls of S1/S1d-deficient mice mature appropriately in the tissue microenvironment of the W/Wv mice. Female W/Wv mice and +/+ controls were immunized with allogeneic spinal cord homogenate in complete Freund's adjuvant and Mycobacterium tuberculosis in order to induce experimental allergic encephalomyelitis. All W/Wv mice developed extensive dermatitis with mastocytosis at the injection sites about 4 months after inoculation. Mast cells were identified by light microscopy following staining with toluidine blue and berberine sulfate as well as electron microscopy. They were also found to be functional since they secreted serotonin and histamine in response to either compound 48/80 or carbachol. The majority of these mast cells were, therefore, considered to be mature, connective tissue like, but many of them were in different stages of granule maturation as seen with electron microscopy. These findings imply that W/Wv mice may not always be appropriate as models of mast cell deficiency. Moreover, these results suggest that the 'defect' in W/Wv mast cell precursors can be overcome by factors produced during immunization and/or development of dermatitis. These findings may, therefore, help elucidate what regulates mast cell maturation/differentiation as well as their pathophysiology.

Activation of bladder mast cells in interstitial cystitis.

Interstitial cystitis (IC) is a sterile, inflammatory bladder condition characterized by urinary frequency and urgency, as well as burning and suprapubic pain, which occurs more frequently in women who may suffer for years before diagnosis. An increased number of mast cells have been associated with IC, but the published reports are inconclusive and often conflicting. Human bladder biopsies were analysed blindly for the degree of activation of mast cells in control and IC patients. It was found that mast cells from IC patients averaged as high as 34 cells/mm2 as compared to less than 16/mm2 in controls. Electron microscopy revealed that over 90% of mast cells from IC patients were activated to various degrees. It is concluded that mast cell activation is a pathologic characteristic for IC.

Mortality rates experience of Kuwait.

PIP: The authors compute the death rate for the population of Kuwait, based on data from Kuwaiti insurance companies, which hitherto have used life tables from the United States and England to compute expected mortality. Graduated mortality rates are introduced, as is a discussion of data adjustment. Finally, Kuwait's new adjusted mortality rates are compared to foreign life tables, and large discrepancies are found. The time period covered is 1985-1989.^ieng