Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antiinflammatory activity of rolipram, a selective inhibitor of the cyclic AMP-specific phosphodiesterase (PDE IV), was studied. Rolipram did not inhibit 5-lipoxygenase activity but did inhibit human monocyte production of leukotriene B4 (LTB4, IC50 3.5 microM). Likewise, murine mast cell release of leukotriene C4 and histamine was inhibited. In vivo, rolipram inhibited arachidonic acid-induced inflammation in the mouse, while the low Km-cyclic-GMP PDE inhibitor, zaprinast, did not inhibit. Rolipram had a modest effect on LTB4 production in the mouse, but markedly reduced LTB4-induced PMN infiltration. Beta-adrenergic receptor activation of adenylate cyclase was important for rolipram antiinflammatory activity since beta blockade abrogated arachidonic acid-induced inflammation. Thus, the antiinflammatory profile of rolipram is novel and may result from inhibition of PMN function and perhaps vasoactive amine release and leukotriene biosynthesis. These actions may be dependent upon endogenous beta-adrenergic activity and are likely mediated through inhibition of PDE IV.
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PMID:Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response. 768 37

We examined the inhibitory effect of DS-4574 (6-(2-cyclohexylethyl)[1,3,4]thiadiazolo[3,2-alpha]-1,2,3- triazolo[4,5-d] pyrimidin-9(3H)-one), a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretion stimulated by several secretagogues in rats. In anesthetized rats with acute gastric fistulas, DS-4574 (50 mg/kg, intraduodenal) significantly inhibited gastric acid secretion induced by both carbachol (50 micrograms/kg, s.c.) and pentagastrin (75 micrograms/kg, s.c.) but not by histamine (2.5 mg/kg, s.c.). In unanesthetized pylorus-ligated rats, DS-4574 (10 and 25 mg/kg, intraduodenal) markedly suppressed increases in gastric acid output and histamine leakage into the gastric juice produced by carbachol (0.1 mg/kg, s.c.) or pentagastrin (1 mg/kg, s.c.). When the relationship between acid output and histamine leakage elicited by carbachol and pentagastrin was assessed, there was a close correlation (r = 0.84) that was highly significant (P < 0.01). In the in vitro study with rat gastric tissues, DS-4574 (10(-7)-10(-5) M) had no effect on the K(+)-dependent ATPase activity or on aminopyrine uptake into mucosal preparations containing parietal cells stimulated by carbachol (10(-5) M), histamine (10(-4) M), or dibutyryl-cyclic AMP (10(-3) M). These results suggest that the effect of DS-4574 may be mediated by inhibition of endogenous histamine from histamine-storing cells in the stomach.
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PMID:Inhibitory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretion in rats. 802 47

Although theophylline has been used in the treatment of lung diseases, particularly bronchial asthma, since the nineteenth century, the mechanisms underlying its effectiveness remained poorly understood until quite recently. The identification of cyclic nucleotide phosphodiesterase (PDE)--the enzyme responsible for breaking down cyclic AMP and cyclic GMP within cells--as a target for methylxanthines such as theophylline led to a research effort that has resulted in the characterization of multiple forms of the PDE enzyme and the development of selective inhibitors for some of these forms. Using these drugs, it has been possible to identify the PDE "isoenzymes" in a number of tissues and cells and to demonstrate the functional effects of the inhibition of different PDEs upon these tissues. Studies on the smooth muscle of human airways and pulmonary arteries have identified isoenzyme-selective PDE inhibitors that are effective broncho- and vasorelaxants in vitro, and it is hoped that these agents may be effective in relieving airway obstruction and pulmonary hypertension in patients. In addition, selective inhibitors of certain PDE isoenzymes suppress the proinflammatory functions of a range of immune cells, including the lung mast cell and the alveolar macrophage. Selective inhibitors of PDE isoenzymes are beginning to undergo clinical trials for the treatment of asthma. The advancing understanding of the PDE distribution in the lung and the ever more precise characterization of distinct enzyme proteins should allow the development of site-selective drugs for the treatment of lung diseases, while minimizing the systemic side effects associated with nonselective PDE inhibitors such as theophylline.
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PMID:Cyclic nucleotide phosphodiesterases in the human lung. 820 28

Increased airway hyperresponsiveness is thought to be one of the phenomena underlying nocturnal airway obstruction in asthma. To investigate the mechanisms that influence and modulate this phenomenon, we compared circadian variations in airway responsiveness with AMP and propranolol with the circadian variation in airway responsiveness to methacholine. Inhalation provocation tests were performed at 16.00 and 04.00 h in 16 nonsmoking atopic asthmatic subjects (18 to 42 yr of age), prospectively assigned to Group 1 (mean circadian peak expiratory flow rate [PEFR] variation > or = 15%) and Group 2 (< 15%). The circadian change in airway responsiveness to AMP, in contrast to methacholine, was significantly related to the circadian PEFR-variation of the 16 subjects (r = 0.81, p < 0.001). In Group 1 (n = 7) geometric mean PC20 AMP decreased more than PC20 methacholine during the night (2.3 and 0.9 doubling concentrations respectively, p < 0.05), whereas no difference in baseline FEV1 was found at the same time points during the different study days. Geometric mean PC20 propranolol did not change during the night. Daytime PC20 propranolol and PC20 AMP, in contrast to PC20 methacholine, were significantly lower in Group 1 as compared with Group 2. Together, the results show a higher susceptibility to stimulation of "indirect" airway responsiveness in the subjects with increased circadian PEFR amplitude. This suggests that mast cell activation rather than primary changes in smooth muscle cell contraction may play a role in the development of nocturnal airway obstruction.
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PMID:Circadian variation in airway responsiveness to methacholine, propranolol, and AMP in atopic asthmatic subjects. 844 80

1. The effects of the alkaloid berberine on basal and stimulated ion transport were investigated in voltage-clamped rat colonic epithelia. 2. Berberine (100-500 microM) reduced basal short circuit current (SCC) when applied basolaterally but not when applied apically. 3. SCC responses to mast cell activation by anti-rat IgE were significantly attenuated in the presence of berberine. 4. Berberine, applied to the basolateral bathing solution, also reduced SCC responses to the following agents which stimulate chloride secretion in rat colon: carbachol, forskolin, sodium nitroprusside, dibutyryl cyclic-AMP, heat-stable E. coli enterotoxin, 8-bromo-cyclic GMP and thapsigargin. Calcium mediated ion transport responses appear to be more sensitive to berberine inhibition than those which are cyclic GMP-mediated, which in turn are more sensitive than cyclic AMP-mediated responses. 5. Berberine added apically was without effect upon forskolin-stimulated ion transport. Cytochalasin D treatment of the lumenal surface of rat colon conferred apical-side sensitivity to berberine. 6. Berberine (at concentrations up to 500 microM) was without effect on generation of cyclic AMP by forskolin or on generation of cyclic GMP by sodium nitroprusside in isolated mucosal segments. Protein kinase A activity stimulated by dibutyryl cyclic AMP was unaffected by berberine (at concentrations up to 500 microM). 7. The precise mechanism of action of berberine remains to be elucidated. However, its site of action appears to be distal to second messenger production and may be at a level common to all stimuli of colonic chloride secretion.
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PMID:Berberine inhibition of electrogenic ion transport in rat colon. 859 Sep 87

1. Recent evidence has implicated eosinophils in the inhibition of allergen-induced rat pleurisy, but the mechanism of this negative modulation is not completely understood. This study was undertaken in order to define the potential role of prostaglandins in this phenomenon. 2. Wistar rats were actively sensitized by subcutaneous injection of a mixture of ovalbumin and AI(OH)3 and challenged with an intrapleural (i.pl.) injection of ovalbumin (12 micrograms/cavity) 14 days later. 3. Analysis of the pleural fluid effluent revealed a massive mast cell degranulation and plasma protein extravasation 4 h post-challenge. We confirmed that concurrently with selective pleural fluid eosinophilia caused by platelet-activating factor (PAF), the pleural cavity became hyporesponsive to allergen-induced protein exudation and to the parallel reduction in the number of intact mast cells. 4. These hyporesponsive animals presented a significant augmentation in the pleural effluent level of prostaglandin E2 (PGE2), which increased with increasing numbers of eosinophils in the pleural cavity. Furthermore, pretreatment with either indomethacin or aspirin failed to modify allergen-induced exudation but reversed the exudatory hyporesponsiveness associated with eosinophil recruitment. 5. Allergic exudation was clearly down-regulated by the following pretreatments: (i) PGE2 (10 micrograms/cavity, i.pl.) plus rolipram (40 micrograms/cavity, i.pl.), (ii) misoprostol (200 micrograms kg-1, p.o.) or (iii) dibutyryl cyclic AMP (80 micrograms/cavity, i.pl.). 6. We conclude that prostaglandins may be implicated in the eosinophil-mediated inhibition of allergic pleurisy, probably acting via cyclic AMP signalling pathway activation.
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PMID:Involvement of prostaglandins in the down-regulation of allergic plasma leakage observed in rats undergoing pleural eosinophilia. 886 61

The chick pineal gland contains histamine and tele-methylhistamine. The levels of both substances are elevated after treatment of chicks with the amino acid precursor of histamine, L-histidine (1 g/kg, ip). In control and L-histidine-loaded animals the pineal levels of histamine and tele-methylhistamine are higher in light-exposed than in dark-adapted animals (measured at the end of the light phase and in the middle of the dark phase of 12 hr light, 12 hr dark illumination cycle, respectively). The chick pineal gland contains histamine-immunofluorescent cells displaying mast cell morphology; they are seen in the vicinity of the capsule and in the parenchyma. Enzymatic studies showed the presence of the activity of histamine synthesizing and inactivating enzyme, i.e., L-histidine decarboxylase (HDC) and histamine-methyltransferase (HMT). The detected enzyme activities were sensitive to specific inhibitors of HDC (alpha-fluoromethylhistidine and alpha-hydrazinohistidine) and HMT (quinacrine and metoprine); inhibitors of aromatic amino acid decarboxylase alpha-methyl-DOPA and NSD-1015 were inactive on HDC. Exogenous histamine added to organ-cultured chick pineals strongly stimulated endogenous cyclic AMP accumulation and moderately increased melatonin secretion. The data, considered collectively, suggest that in avians histamine, probably originating from the pineal mast cell compartment, may function as a regulator of pineal gland activity.
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PMID:Histamine in the chick pineal gland: origin, metabolism, and effects on the pineal function. 906 67

In addition to the autonomic nervous system and gut hormones, the mast cell mediator histamine has also been associated with exocrine pancreatic secretion. This review is concerned with the distribution and the physiological role of histamine in the control of pancreatic juice secretion. Histamine is distributed widely around blood vessels and acinar tissues in the pancreas and it is released in pancreatic juice during secretagogue stimulation. Histamine has a marked secretagogue effect in the exocrine pancreas of several animal species but in many cases the secretory effect is gender-related. The paracrine hormone exerts its secretory response via activation of H1 and H2 receptors on pancreatic acinar cells to mobilize potassium ions (K+) and cellular calcium (Ca2+) and through elevation of endogenous adenosine 3',5' cyclic monophosphate (cyclic AMP) levels, respectively. A physiological role for H3 receptors has also been associated with exocrine pancreatic secretion. H3 receptors are located presynaptically on parasympathetic nerve terminals to control the release of acetylcholine via restriction of Ca2+ access into nerve terminal through the N-type Ca2+ channel. Taken together, the results presented in this review strongly support histamine as a potential modulator of exocrine pancreatic function.
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PMID:The physiological role of histamine in the exocrine pancreas. 919 85

We investigated the mechanism by which inosine, a metabolite of adenosine that accumulates to > 1 mM levels in ischemic tissues, triggers mast cell degranulation. Inosine was found to do the following: (a) compete for [125I]N6-aminobenzyladenosine binding to recombinant rat A3 adenosine receptors (A3AR) with an IC50 of 25+/-6 microM; (b) not bind to A1 or A2A ARs; (c) bind to newly identified A3ARs in guinea pig lung (IC50 = 15+/-4 microM); (d) lower cyclic AMP in HEK-293 cells expressing rat A3ARs (ED50 = 12+/-5 microM); (e) stimulate RBL-2H3 rat mast-like cell degranulation (ED50 = 2.3+/-0.9 microM); and (f) cause mast cell-dependent constriction of hamster cheek pouch arterioles that is attenuated by A3AR blockade. Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth muscle and inhibit mast cell degranulation. The A3 selectivity of inosine may explain why it elicits a monophasic arteriolar constrictor response distinct from the multiphasic dilator/constrictor response to adenosine. Nucleoside accumulation and an increase in the ratio of inosine to adenosine may provide a physiologic stimulus for mast cell degranulation in ischemic or inflamed tissues.
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PMID:Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. 938 51

Characterization of A2B receptors is hampered by the lack of selective pharmacological probes and often relies on their relative affinity to agonists that are selective at other receptor types. This approach is limited because the affinity of A2B receptors for putative A3 agonists has not been determined. Using the human erythroleukemia cell line HEL as a cellular model for A2B-mediated adenylate cyclase activation, we found the following potencies (pD2) for the non-selective agonist 5'-N-ethylcarboxamidoadenosine (NECA) (5.65 +/- 0.04), the putative A3 agonists N6-benzyl-NECA (4.17 +/- 0.06) and N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (IB-MECA) (3.7 +/- 0.02), and the A2A agonist 4-[(N-ethyl-5'-carbamoyladenos-2-yl)-aminoethyl]-phenylpropionic acid (CGS21680) (2.8 +/- 0.1). Because of the lack of a selective agonist, characterization of A2B receptor function is difficult in cells co-expressing A2A receptors. In the human mast cell line HMC-1, NECA induced cAMP accumulation with a concentration-response relationship best fitted to a two-sited model (pD2 7.69 +/- 0.42 and 5.92 +/- 0.21 for high- and low-affinity sites), suggesting the presence of both A2A and A2B receptors in these cells. We demonstrated that A2B receptors can be selectively activated with NECA in the presence of the selective A2A antagonist 5-amino-7-(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c ]pyrimidine (SCH 58261). Under these conditions, the concentration-response relationship of NECA for cyclic AMP accumulation was now best fitted to a one-site model (pD2 5.68 +/- 0.03, Hill slope 0.93 +/- 0.06, 95% confidence intervals 0.8 to 1.06) corresponding to selective activation of A2B receptors. Using the approaches developed in this study, we determined that A2B, and not A2A or A3, receptors account for all the calcium mobilization induced by NECA in HMC-1 cells.
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PMID:Pharmacological characterization of adenosine A2B receptors: studies in human mast cells co-expressing A2A and A2B adenosine receptor subtypes. 951 73


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