Subject(s)
Histamine Release/physiology , Platelet Aggregation/physiology , Animals , Humans , In Vitro Techniques , Male , Mast Cells/physiology , Rats , Rats, Inbred StrainsABSTRACT
Experiments were carried out to provide further information on the biochemical and morphological changes occurring in the guinea-pig heart after multiple ligature and reopening of the left anterior descending (LAD) coronary artery. In isolated perfused guinea-pig heart the reopening of LAD coronary artery leads to a release of histamine related to a loss of metachromasia by cardiac mast cells. The process is associated with malonyldialdehyde (MDA) production, cellular overload of calcium and ventricular arrhythmias which can be modulated by pharmacological interventions.
Subject(s)
Heart/physiopathology , Histamine Release/drug effects , Myocardial Reperfusion Injury/physiopathology , Myocardium/metabolism , Animals , Coronary Vessels/physiology , Guinea Pigs , Heart/drug effects , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Male , Mast Cells/drug effects , Mast Cells/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardium/cytology , Myocardium/enzymologyABSTRACT
Coincubation of rat serosal mast cells with human platelets leads to a significant release of histamine. which dose-dependently increases when platelet aggregation is induced by various concentrations of arachidonic acid. In turn, histamine enhances platelet aggregation induced by different agonists, this effect being mimicked by pyridyl-ethyl-amine (PEA), blocked by mepyramine and amplified by ranitidine. The data suggest the existence of a platelet-derived histamine releasing factor (PDHRF) and indicate the presence of platelet H1 and H2 receptors, capable of modulating platelet aggregation.
Subject(s)
Blood Platelets/metabolism , Histamine Release/drug effects , Mast Cells/metabolism , Platelet Aggregation/drug effects , Animals , Arachidonic Acids/pharmacology , Blood Platelets/enzymology , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Male , Mast Cells/enzymology , Pyridines/pharmacology , Pyrilamine/pharmacology , Ranitidine/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
Polyunsaturated fatty acids (PUFA: arachidonic and linoleic acid) release histamine from isolated purified rat serosal mast cells only in the presence of oxidizing systems such as phenobarbital-induced rat liver microsomes, prostaglandin-H-synthetase (PHS) or soybean lipoxygenase. The release of mast cell histamine by activated PUFA has a long time-course and the electron microscopical features are consistent with an exocytotic secretion in the case of arachidonic acid and cell lysis in the case of linoleic acid. The phenomenon is associated with a significant increase in malonyldialdehyde (MDA) and conjugated diene generation, suggesting a relationship between histamine release and membrane lipid peroxidation. The secretion of histamine was inhibited by anti-free radical interventions such as D-mannitol, reduced glutathione and alpha-tocopherol. Some cyclooxygenase and lipoxygenase inhibitors, cimetidine and carnitine derivatives, are differentially active in the inhibition of mast cell histamine release by activated arachidonic acid. These results suggest that free radical derivatives of PUFA, generated by metabolic activation, trigger mast cell histamine release.
Subject(s)
Arachidonic Acids/pharmacology , Histamine Release/drug effects , Linoleic Acids/pharmacology , Mast Cells/drug effects , Animals , Arachidonic Acid , Arachidonic Acids/pharmacokinetics , Biotransformation/drug effects , Free Radicals , L-Lactate Dehydrogenase/metabolism , Linoleic Acid , Linoleic Acids/pharmacokinetics , Lipid Peroxidation , Male , Mast Cells/metabolism , Mast Cells/pathology , Phenobarbital/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
Free radicals produced by the occlusion and opening of the left anterior descending coronary artery and/or by perfusion of isolated guinea-pig heart with FeCl3/ADP (10 microM/100 microM) induce a differential release of histamine and lactate dehydrogenase (LDH) in the perfusates with a preferential liberation of histamine in the reperfusion phase, associated with an increase of ventricular arrhythmias. The release of histamine has been correlated with malonyldialdehyde (MDA) production and tissue calcium content in left ventricular tissue. MDA increased during ischemia, while the calcium content increased when the tissue was reperfused. Under these conditions, N-t-butyl-alpha-phenylnitrone (BPN), a molecule capable of forming spin adducts with free radicals, and D-mannitol are active in preventing reperfusion-induced arrhythmias.
Subject(s)
Coronary Disease/immunology , Histamine Release , Myocardial Reperfusion Injury/immunology , Animals , Coronary Disease/metabolism , Free Radicals , Guinea Pigs , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Male , Malondialdehyde/metabolism , Myocardial Reperfusion Injury/metabolism , PerfusionABSTRACT
In isolated rat serosal mast cells exposed to free radical-generating systems, the release of histamine was associated with a significant increase in malonyldialdehyde (MDA) production suggesting a relationship between histamine release and membrane lipid peroxidation. Under these circumstances, an increase in cytosolic calcium was observed, uncoupled with any stimulation of inositol phospholipid (PtdIns) breakdown. The data suggest similarities between the release of histamine induced by calcium ionophores and by free radical-generating systems.
Subject(s)
Histamine Release , Signal Transduction , Animals , Calcimycin/pharmacology , Free Radicals , Histamine Release/drug effects , In Vitro Techniques , Male , Malondialdehyde/metabolism , Mast Cells/drug effects , Mast Cells/metabolism , Mast Cells/physiology , Rats , Rats, Inbred Strains , Signal Transduction/drug effects , p-Methoxy-N-methylphenethylamine/pharmacologyABSTRACT
2-Pyrrolidone-5-carboxylic acid (PCA) is a cyclic derivative of glutamic acid, physiologically present in mammalian tissues. We herein report preclinical pharmacology experiments showing that PCA releases GABA from the cerebral cortex of freely-moving guinea-pigs and displays anti-anxiety effects in a simple approach-avoidance conflict situation in the rat. In clinical pharmacology experiments, PCA significantly shortens the plasma half-life of ethanol during acute intoxication. In chronic alcoholics a treatment with PCA (2g/day per 30 days) significantly hastens the recovery to physiological values of plasma gamma-glutamyl transferase activity and of the urinary excretion of glucaric acid, which are considered suitable markers of the trend of the alcoholic disease. The evidence emerging from preclinical and clinical studies strongly suggests that, by combining central anxiolytic actions with the peripheral recovery of the antioxidant defense system in the liver, PCA should be further investigated as an interesting endogenous molecule possibly helpful in the therapy of alcoholism.
Subject(s)
Alcoholic Intoxication/physiopathology , Alcoholism/physiopathology , Pyrrolidinones/pharmacology , Pyrrolidonecarboxylic Acid/pharmacology , gamma-Aminobutyric Acid/metabolism , Alcoholic Intoxication/blood , Alcoholism/blood , Animals , Ethanol/blood , Female , Guinea Pigs , Humans , Male , RatsABSTRACT
Free radicals are produced by perfusion of isolated guinea pig heart with FeCl3/ADP (10 microM/100 microM) and/or occlusion and opening of the left anterior descending coronary artery. Cardiac histopathology was correlated with histamine and lactate dehydrogenase release and with malondialdehyde production. A differential release of histamine and lactate dehydrogenase in the perfusate was detected, showing a preferential liberation of histamine in the reperfusion phase. The increase in lipid peroxidation product in left ventricular tissues after left coronary artery occlusion was maximal at the end of ischemia.
Subject(s)
Histamine Release , Myocardium/metabolism , Oxygen/toxicity , Reperfusion Injury/metabolism , Adenosine Diphosphate/pharmacology , Animals , Chlorides , Ferric Compounds/pharmacology , Free Radicals , Guinea Pigs , L-Lactate Dehydrogenase/metabolismABSTRACT
In isolated rat serosal mast cells, studies with the fluorescent Ca2+ indicator, quin 2, and with [3H]-myoinositol to label endogenous polyphosphoinositides have established that an increase in cytosol Ca2+ levels was obligatory for histamine release by free radicals. No substantial breakdown of phosphatidylinositol and related polyphosphoinositides was associated with generation of the Ca2+ signal and histamine release, suggesting that the release of histamine by free radicals entails different pathways than the calcium-mobilizing receptors linked to polyphosphoinositides as second messengers.
Subject(s)
Calcium/physiology , Histamine Release , Oxygen/pharmacology , Phosphatidylinositols/physiology , Animals , Biotransformation , Free Radicals , In Vitro Techniques , Mast Cells/physiology , Prostaglandin-Endoperoxide Synthases/metabolism , Rats , Xenobiotics/metabolismABSTRACT
Calcium antagonists have been reported to exert protective effects in hypersensitivity reactions in man and animals. However, their effect on anaphylactic histamine release is highly variable and controversial. In the present paper we evaluate the effect of calcium entry blockers and BAY K 8644 on the response to specific antigen in isolated hearts taken from actively sensitized guinea-pigs and from isolated rat and guinea-pig mast cells, actively or passively sensitized. Verapamil, diltiazem, nifedipine and prenylamine dose-dependently decreased anaphylactic histamine release in isolated actively sensitized guinea-pig mast cells. BAY K 8644 was found to be ineffective. In isolated, passively sensitized rat mast cells, verapamil showed a highly significant inhibitory effect, while prenylamine (10(-4) M) was able to evoke a histamine releasing effect. In cardiac anaphylaxis verapamil, diltiazem, prenylamine, but not nifedipine, were active in reducing the release of histamine without modifying the antigen-induced arrhythmias and positive chronotropic and inotropic effects.
Subject(s)
Calcium Channel Blockers/pharmacology , Histamine Release/drug effects , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Anaphylaxis/immunology , Animals , Female , Guinea Pigs , Heart/drug effects , In Vitro Techniques , Male , Mast Cells/drug effects , Mast Cells/immunology , Myocardium/immunology , RatsABSTRACT
It has been shown that plasma histamine significantly increases during myocardial infarction in the dog. Histamine is also released when the isolated guinea-pig heart is reperfused after 30 minutes of low flow perfusion. The release of histamine and lactate dehydrogenase (LDH) after left anterior descending coronary artery ligation and release were investigated in the present study and related to the changes in electrocardiographic parameters and to a computer-aided analysis of left ventricular mast cell metachromasia. Spontaneous release of histamine was unchanged during ischemia and increased after the release of the ligature, while we observed a steady increase of LDH overflow. In parallel, a significant diminution of mast cell granule metachromasia was observed in left ventricular samples. The perfusion of the heart with FeCl3/ADP (10 microM/100 microM), a free radical-generating system, significantly enhanced both the basal and ischemic-reperfusion release of histamine, while perfusion with N-t-butyl-phenyl-nitrone (BPN/100 microM) a "spin-trapper" molecule, significantly decreased histamine and LDH release and the loss in metachromasia of left ventricular mast cells induced by reperfusion. Inhibitors of xanthine oxidase (allopurinol, 10 microM) and of calcium-activated proteases (leupeptin, 10 microM) modified the kinetics of histamine and LDH release.
Subject(s)
Coronary Disease/immunology , Histamine Release , Animals , Coronary Disease/enzymology , Guinea Pigs , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Male , Myocardium/enzymology , Myocardium/immunology , PerfusionABSTRACT
In the present paper we report the results of experiments carried out to measure the release of histamine from isolated rat mast cells during the metabolic activation of arachidonic acid. Arachidonic acid (10(-8)-10(-4) M) and the terminal products (10(-6) M) of the arachidonic acid pathways were devoid of any significant histamine releasing properties. A substantial amount of histamine was released from rat mast cells by low concentrations of arachidonic acid during incubation with prostanoid generating systems, such as guinea-pig lung microsomes, rat serosal macrophages and polymorphonuclear cells and prostaglandin-H-synthase from calf seminal vesicles. The release of histamine was not accompanied by a leakage of lactate dehydrogenase and was blocked by D-mannitol and by lipoxygenase and cyclooxygenase pathway inhibitors. The data are consistent with the hypothesis that free radical derivatives of arachidonic acid, originating from hydroperoxy fatty acids, are generated during catalysis, causing mast cell histamine release.
Subject(s)
Arachidonic Acids/metabolism , Histamine Release , Mast Cells/metabolism , Animals , Arachidonic Acid , In Vitro Techniques , Macrophages/metabolism , Male , Microsomes/metabolism , Neutrophils/metabolism , Rats , Rats, Inbred StrainsABSTRACT
This study was performed to evaluate the role of intermediate products of arachidonic acid metabolism on histamine release from rat serosal mast cells. Arachidonic acid in concentrations ranging from 10(-9) to 10(-4) M caused no histamine release from purified rat peritoneal mast cells. High concentrations (10(-6)-10(-6) M) of the terminal products of the arachidonic acid metabolism were also devoid of any significant histamine-releasing properties. The metabolic activation of arachidonic acid with prostaglandin-H-(PGH)-synthase isolated from calf seminal vesicles, evoked a significant release of histamine from rat serosal mast cells. The liberation of histamine was not accompanied by a significant leakage of lactic dehydrogenase (LDH) and the electron microscopical features were consistent with an exocytotic release. The phenomenon was blocked by reduced glutathione (GSSH) and by D-mannitol, a hydroxyl free-radical scavenger. These results suggest that free radical derivatives of arachidonic acid are generated during the catalysis which triggers mast cell histamine release.
