Mepyramine inhibits platelet activating factor-induced rabbit platelet aggregation: role of intracellular histamine.
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AIM: To study the possible role of intracellular histamine (HA) in platelet activating factor (PAF)-induced platelet activation. METHODS: Washed rabbit platelet suspension was used to test the inhibitory effect of mepyramine (Mep, an H1 receptor antagonist) on PAF-induced platelet aggregation. The thromboxane B2 (TXB2) generation was measured by radioimmunoassay and the intracellular calcium ([Ca2+]i) concentration was determined by the specific fluorescence indicator Fura-2. RESULTS: Mep > 100 mumol.L-1 generated a concentration-dependent inhibition on PAF-induced aggregation, with an IC50 value of 162 (95% confidence limits: 114-232 mumol.L-1). Cimetidine, an H2 receptor antagonist, even up to 400 mumol.L-1 had no effect on it. Exogenous HA (10 mumol.L-1) and H1 receptor agonist, 2-thiazolylethylamine had no energetic effect. alpha-Fluoromethylhistidine, an inhibitor of histidine decarboxylase, did not inhibit platelet responses. However, in platelets permeabilized with saponin (8-10 mg.L-1), exogenous HA attenuated the inhibitory effect of Mep to about 50% at a concentration of 50 mumol.L-1. Preincubation of platelets with Mep (100 or 200 mumol.L-1) resulted in an inhibition on TXB2 generation and [Ca2+]i elevation induced by PAF. CONCLUSION: Platelets activated by PAF is associated with an intracellular HA synthesis and release via a common pathway of TXB2 generation and the rise of [Ca2+]i. (+info)
Histamine aggravated levothyroxine-induced cardiomyopathy in guinea pigs.
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AIM: To study effects of histamine on cardiomyopathy. METHODS: Cardiomyopathy model was developed in guinea pig by i.p. levothyroxine 0.5 mg.kg-1.d-1 for 10 d. Langendroff's hearts were perfused. ECG and contractile force were recorded. Histamine (5 micrograms) was given by intra-aortic injection. Histamine content of coronary venous effluent was determined fluorometrically. RESULTS: Attack of histamine on cardiomyopathy was severer than that in normal hearts. Tachycardia was more prominent; atrioventricular conduction block occurred earlier; decrease in coronary flow was more marked. Uptakes of histamine were 37% in the model and 19% in the normal hearts (P < 0.01). CONCLUSION: Histamine aggravated levothyroxine-cardiomyopathy. (+info)
Molecular forceps from combinatorial libraries prevent the farnesylation of Ras by binding to its carboxyl terminus.
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INTRODUCTION: Ras is one of the major oncogenes. In order to function properly it has to undergo post-translational processing at its carboxyl terminus. It has been shown that inhibitors of farnesyl transferase, the first enzyme in the processing chain, can suppress the transforming activity of oncogenic Ras. RESULTS: We have identified molecular forceps, branched peptidic molecules, from combinatorial libraries that bind to the carboxyl terminus of Ras and interfere with its farnesylation without inhibiting the farnesyl transferase. The active molecules were selected by a screening against the carboxy-terminal octapeptide of Ras. CONCLUSIONS: The implications of our findings are twofold. First, we demonstrate that it is possible to prevent enzymatic transformations by blocking the enzyme's access to its substrate using a synthetic small molecule to mask the substrate. Second, we show that it is feasible to derive molecules from combinatorial libraries that bind a specific epitope on a protein by selecting these molecules with the isolated peptide epitope. (+info)
Lack of histamine synthesis and down-regulation of H1 and H2 receptor mRNA levels by dexamethasone in cerebral endothelial cells.
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The purpose of this work was to determine whether cerebral endothelial cells have the capacity to synthesize histamine or to express mRNA of receptors that specifically respond to available free histamine. The histamine concentrations and the expression of L-histidine decarboxylase (HDC) and histamine H1 and H2 receptor mRNA, both in adult rat brain and in cultured immortalized RBE4 cerebral endothelial cells, were investigated. In this study endothelial cells were devoid of any kind of detectable histamine production, both in vivo and in the immortalized RBE4 cells in culture. Both the immunostainings for histamine and the in situ hybridizations for HDC were negative, as well as histamine determinations by HPLC, indicating that endothelial cells do not possess the capacity to produce histamine. Also, glucocorticoid (dexamethasone) treatment failed to induce histamine production in the cultured cells. Although the cerebral endothelial cells lack histamine production, a nonsaturable uptake in RBE4 cells is demonstrated. The internalized histamine is detected both in the cytoplasm and in the nucleus, which could indicate a role for histamine as an intracellular messenger. Histamine H1 and H2 receptor mRNA was expressed in RBE4 cells, and glucocorticoid treatment down-regulated the mRNA levels of both H1 and H2 receptors. This mechanism may be involved in glucocorticoid-mediated effects on cerebrovascular permeability and brain edema. (+info)
Role of nitric oxide in the regulation of microvascular perfusion in human skin in vivo.
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1. Nitric oxide (NO) concentrations were measured in dialysate from healthy human skin, in vivo, both at rest and during the inflammatory response to intradermal histamine or bradykinin. Changes in dialysate NO concentration, measured by electrochemical detection, were related to changes in dermal vascular perfusion, measured using scanning laser Doppler imaging. 2. Basal NO concentration in dermal microdialysate was 0.60 +/- 0.14 microM (mean +/- s.e.m.). Following the intradermal injection of histamine, a transient, time-dependent increase in NO concentration was measured in areas of skin incorporating the weal and in others incorporating the flare. The increase in NO concentration was associated with an increase in dialysate cGMP concentration in both the weal and flare areas. 3. Addition of N G-nitro-l-arginine-methyl ester (L-NAME, 5 mM) to the probe perfusate resulted in an inhibition of the histamine-induced increase in NO and cGMP. Moreover, the reduction in dialysate NO concentration was associated with a reduction in dermal vascular flux, both under basal conditions and within the weal and flare response. 4. These results demonstrate, by the use of microdialysis, that vasoactive mediators can be measured in healthy human skin in vivo. They provide direct evidence that endogenous concentration of NO increases during the inflammatory weal and flare response to histamine and that the increase in dermal NO concentration is associated with increases in cGMP concentration and dermal vascular perfusion, thus confirming a role for NO in vasoregulation in human skin. (+info)
Effects of calcium-antagonistic drugs on the stimulation by carbamoylcholine and histamine of phosphatidylinositol turnover in longitudinal smooth muscle of guinea-pig ileum.
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A number of drugs classed as calcium antagonists, spasmolytics, non-specific receptor antagonists or receptor antagonists with multiple sites of action were tested to determine whether they prevent the stimulation of phosphatidylinositol turnover caused in various tissues by the activation of receptors which increase cell-surface Ca2+ permeability. The experiments were done with fragments of longitudinal smooth muscle from guinea-pig ileum; these were incubated in vitro with 32Pi and either 100 muM-carbamoylcholine or 100 muM-histamine, in the presence of antagonistic drugs at concentrations at least sufficient to cause complete blockade of smooth-muscle contraction. The phosphatidylinositol response to carbamoylcholine was not changed by cinchocaine, papaverine, nifedipine, dibenamine, amethocaine, cinnarizine, lidoflazine, methoxyverapamil, prenylamine or two antimuscarinic alkane-bis-ammonium compounds, and the response to histamine was unaffected by the first four drugs. In contrast, phenoxybenzamine prevented the increase in phosphatidylinositol labelling caused by either carbamoylcholine or histamine. The insensitivity of the phosphatidylinositol response to most of the drugs provides further experimental support for the conclusion that the receptor-stimulated phosphatidylinositol breakdown which initiates the increase in phosphatidylinositol turnover is not caused by an increase in intracellular Ca2+. The simplest interpretation of the available information appears to be that phosphatidylinositol breakdown plays a role in the coupling between the receptor-agonist interaction and the opening of cell-surface Ca2+ gates [Michell, R. H. (1975) Biochim. Biophys. Acta 415, 81-147]. If this is correct, then phenoxybenzamine must exert its inhibitory effects on phosphatidylinositol breakdown early in this sequence of events, but the drugs must act at a stage later than phosphatidylinositol breakdown. The unexpected difference in the effects of dibenamine and phenoxybenzamine, which are chemically very similar, may provide a useful experimental tool with which to explore the way in which activated receptors provoke the opening of cell-surface Ca2+ gates. (+info)
Decreased vascular reactions to permeability factors in experimental diabetes.
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Light and electron microscopic studies showed that blood vessels of the cremaster muscle of alloxan-diabetic rats under the local influence of histamine or serotonin presented less labelling by colloidal carbon, previously injected i.v., than vessels of normal rats. The hyporeactive state of these vessels was promptly reversed to normal conditions by the administration of insulin. Insulin also potentiated leakage of carbon particles in the vessels of normal animals. These findings add new evidence that insulin might be involved in vascular events following injury and that decreased levels of the hormone, as occurring in diabetes, might result in decreased inflammatory reactions. (+info)
Effect of inhaled corticosteroids on bronchial responsiveness in patients with "corticosteroid naive" mild asthma: a meta-analysis.
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BACKGROUND: Inhaled corticosteroids are the most efficacious anti-inflammatory drugs in asthma. International guidelines also advocate the early introduction of inhaled corticosteroids in corticosteroid naive patients. A study was undertaken to assess the effects of inhaled corticosteroids on bronchial hyperresponsiveness in patients with corticosteroid naive asthma by conventional meta-analysis. METHODS: A Medline search of papers published between January 1966 and June 1998 was performed and 11 papers were selected in which the patients had no history of treatment with inhaled or oral corticosteroids. Bronchial responsiveness to bronchoconstricting agents was considered as the main outcome parameter. Doubling doses (DD) of histamine or methacholine were calculated. RESULTS: The total effect size of inhaled corticosteroids (average daily dose 1000 microg) versus placebo in the 11 studies was +1.16 DD (95% confidence interval (CI) +0.76 to +1.57). When only the eight short term studies (2-8 weeks) were analysed the effect size of the bronchoconstricting agent was +0.91 DD (95% CI +0.65 to +1.16). No relationship was found between the dose of inhaled corticosteroid used and the effect on bronchial responsiveness. CONCLUSION: This meta-analysis in patients with corticosteroid naive asthma indicates that, on average, high doses of inhaled corticosteroids decrease bronchial hyperresponsiveness in 2-8 weeks. It remains unclear whether there is a dose-response relationship between inhaled corticosteroids and effect on bronchial hyperresponsiveness. (+info)