Vancomycin-induced release of histamine from rat peritoneal mast cells and a rat basophil cell line (RBL-1).

Rapid intravenous administration of the glycopeptide antibiotic, vancomycin, may cause a hypotensive reaction which can usually be prevented by infusing vancomycin in dilute solutions. The release of histamine from circulating cells such as basophils and tissue mast cells has been implicated in hypotensive reactions since the effects can be prevented by antihistamine pretreatment. The direct effects of vancomycin on histamine release were therefore investigated in rat peritoneal mast cells and rat leukemic basophils (RBL-1 cells). Suspension cultures of mast cells or RBL-1 cells were exposed to vancomycin for 30-60 minutes at concentrations comparable to those infused clinically (2.28 or 4.56 mg/ml). Vancomycin induced a time- and dose-dependent release of histamine into the culture media from both cell types. The reference degranulating agent, Compound 48/80 (CP 48/80), was also shown to induce histamine release from mast cells and RBL-1 cells. Mast cells were significantly more sensitive to vancomycin and CP 48/80 than RBL-1 cells and, unlike RBL-1 cells, were responsive to the inhibitory effects of cromolyn sodium on histamine release. Cromolyn sodium did not inhibit vancomycin-induced histamine release in RBL-1 or mast cells. Morphologically, mast cells exposed to either vancomycin or CP 48/80 exhibited dose-related degranulation. On the other hand, treatment-related degranulation effects of either vancomycin or CP 48/80 on RBL-1 cells could not be reliably distinguished from controls by qualitative evaluation. Based upon these findings it is concluded that mast cells may represent a more useful model to evaluate the potential of investigational agents to release histamine and to study mechanisms of histamine release than RBL-1 cells.     

Effect of nociceptin on histamine and serotonin release in the central nervous system

Role in pain sensation of both nociceptin (NC), the bioactive heptadecapeptide sequence of preproorphaninFQ and of histamine has been widely evidenced in the central nervous system (CNS). In the current series of experiments effect of intracerebroventricularly (i.c.v.) administered NC (5.5 nmol/rat) on histamine and serotonin levels in blood plasma, CSF and brain areas (hypothalamus and hippocampus) was studies and compared to the effect of the mast cell degranulator Compound 48/80(100microg/kg, i.c.v.) and the neuroactive peptide Substance P (50nmol/rat, i.c.v.). It was found that all the three compounds increased the histamine level in the CNS, however their activity concerning the mast cell-, and neuronal histamine release is different. NC could release histamine from both the mast cells and the neurons and it decreased CNS serotonin levels. Substance P was found the most potent in increasing CNS histamine levels. Compound 48/80 treatment resulted in elevated histamine levels both in the CNS and blood plasma. It is concluded that the histamine releasing effects of i.c.v. administered NC and SP are limited to the CNS, but in the effect of Compound 48/80 its blood-brain barrier impairing activity is also involved. Data also demonstrate that NC has significant effect on both the histaminergic and serotonergic neurotransmission in the CNS.     

Potassium-induced release of tritiated histamine from rat brain tissue slices.

The release of exogenous histamine was studied by superfusing brain slices following incubation with the radiolabeled amine. Histamine was released in a calcium-dependent way by 40 mM potassium. This release was high in hypothalamus and striatum and low in hippocampus and cortex. Compound 48/80, a mast cell histamine releasing agent, also induced histamine release, but only from hypothalamic tissue slices. It is suggested that the potassium-induced release of accumulated exogenous histamine is mainly from glial cells.     

Histamine-releasing properties of Polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog

The solvent of commercial amiodarone (Polysorbate 80) has been reported to produce haemodynamic responses in humans and in dogs similar to those produced by histamine infusion. We therefore evaluated the correlation between hypotension induced by the solvent of amiodarone and its histamine-releasing properties in the awake dog. The solvent of amiodarone administered to a dog, over 5 min in a dose of 10 mg/kg of Polysorbate 80, produced severe hypotension after the first administration; the second injection (24 h later) caused fewer hypotensive effects. Histamine release in the peripheral tissues was demonstrated by a marked increase in plasma histamine concentrations, with the maximum value 10 min after the solvent administration. H1- and H2-receptor blockade with mepyramine (5 mg/kg) and cimetidine (10 mg/kg) significantly reduced the cardiovascular effects of the solvent. Isolated peritoneal mast cells from rats also released histamine in response to Polysorbate 80. These studies show that Polysorbate 80 releases histamine both in vitro and in isolated mast cells from rats and in vivo in the dog, and that the plasma concentrations are correlated with the haemodynamic responses.     

Increase of plasma renin activity after subcutaneous application of compound 48/80 in the rat

Subcutaneous (s.c.) administration of compound 48/80 (3.0 mg/kg) to conscious rats produced a time-dependent long-lasting increase of plasma renin activity (PRA). A dose-related increase of the hematocrit was also observed after injection of compound 48/80. The onset of the hematocrit increase preceded that of PRA increase. Pretreatment with a dose of more than 20 mg/kg of histamine H1-receptor antagonists such as tripelennamine or diphenhydramine prior to the injection of compound 48/80 (3.0 mg/kg s.c.) attenuated or abolished the effects of compound 48/80 on PRA, hematocrit and plasma extravasation. Pretreatment with cimetidine (histamine H2-receptor antagonist, 40 mg/kg i.p.) had no effect on these plasma variables. The increase of PRA caused by s.c. administration of compound 48/80 was not affected by the pretreatment with propranolol (beta-adrenoceptor antagonist, 10 mg/kg i.p.), which completely inhibited the isoproterenol (0.5 mg/kg s.c.)-induced PRA increase. Administration of compound 48/80 did not induce a significant PRA increase in the nephrectomized rats although the increase of hematocrit following s.c. administration of compound 48/80 persisted despite the absence of kidneys. S.c. administration of compound 48/80 (3.0 mg/kg) led to a significant decrease of histamine content at the site of injection and to a significant increase in plasma histamine concentration without affecting arterial blood pressure. The present data suggest that s.c. administration of compound 48/80 stimulates the release of histamine from cutaneous mast cells, which cause an increase in vascular permeability to plasma protein via the stimulation of histamine H1-receptors, then leads to hypovolemia. The resulting hypovolemia may directly stimulate the juxtraglomerular cells of the kidney to release renin.     

Effects of drugs acting as histamine releasers or histamine receptor blockers on an experimental anxiety model in mice

Experimental anxiety in mice was evaluated using a light/dark test at 60 min after injection of various histaminergics. Thioperamide, a histamine H(3) receptor inhibitor (5-20 mg/kg, intraperitoneal [IP]), Compound 48/80, a mast cell degranulator (0.1-10 microg/2 microl, intracerebroventricularly [ICV]), mepyramine, a histamine H(1) receptor antagonist (0.1-10 microg/2 microl, ICV) or cimetidine, a histamine H(2) receptor antagonist (0.1-10 microg/2 microl, ICV) alone did not affect the locomotive activity, the time spent in the light zone, and number of shuttle crossings in the light/dark test. However, the time spent in the light zone and the number of shuttle crossings significantly decreased only when cimetidine (0.1-10 microg/2 microl, ICV) was co-treated with either thioperamide (10 mg/10 ml/kg, IP) or Compound 48/80 (1.0 microg/2 microl, ICV). The decrease in these behavioral parameters suggests induced experimental anxiety in mice. The experimental anxiety was antagonized by mepyramine (10 microg/2 microl, ICV). These results suggest that not only neuronal histamine release induced by thioperamide but also non-neuronal (mast cells) histamine release induced by Compound 48/80 play an important role in inducing experimental anxiety via post-synaptic H(1) and H(2) receptors. In addition, it is likely that the anxiety may be mediated by the stimulation of H(1) receptors, while H(2) receptors may inhibit the anxiety produced by the activation of H(1) receptors.     

Plasma histamine and catecholamine levels during hypotension induced by morphine and compound 48/80

Histamine receptors are present in adrenergic terminals, and histamine is reported to inhibit release of the neurotransmitter norepinephrine (NE) at certain neuroeffector junctions. However, a physiological role for histamine in modifying adrenergic neurotransmission has not been established. To examine the interaction of elevated plasma histamine and catecholamine release, two compounds that release histamine, morphine (3 mg/kg), and compound 48/80 (0.5 mg/kg), were administered intravenously (i.v.). Plasma norepinephrine (NE) levels were used to monitor sympathetic nervous system activity, and plasma epinephrine (Epi) levels were used to monitor adrenal activity. Both morphine and compound 48/80 caused an immediate and marked increase in plasma histamine. Simultaneous with this increase, a marked decrease in mean arterial pressure occurred. Plasma NE levels increased in animals administered compound 48/80, but in morphine-treated animals, plasma NE levels did not change from pretreatment values. Plasma Epi levels increased in both groups, but the magnitude and duration of the responses differed. The results indicate that elevated plasma catecholamines can increase in response to histamine-induced hypotension but this effect can be suppressed by the central actions of morphine.     

Alterations in histamine levels in the rat induced by compound 48/80

Histamine release in the rat was induced in vivo either by a single dose of compound 48/80 injected i.v. or by four repeated, daily doses of the same compound injected i.p. After i.v. injection the levels of blood histamine were determined and after i.p. injections the changes in both tele-methylhistamine and histamine levels in different tissues were investigated. I.v. injection of 48/80 induced a very rapid and marked increase of blood histamine by 7.4 to 11-fold over the control levels within the first two minutes. After repeated i.p. injections of compound 48/80 most tissues showed higher than normal tele-methylhistamine/histamine ratios. The results suggest that agents known to induce release of histamine from mast cells may exert significant changes in blood and tissue histamine levels and that liberated histamine is thereafter extensively catabolized.     

Mechanisms of histamine release by compound 48/80

1. Rat and guinea-pig lung tissues were incubated for 20 min at 37 degrees C in Krebs-Ringer phosphate buffer at pH 7.4, or in Tyrode-Tris buffer at pH 8.2, and the release of histamine produced by adding different concentrations of compound 48/80 to the incubation medium was determined.2. At pH 7.4, increasing concentrations of 48/80 increased the release of histamine from the rat lung, with a tendency towards a maximum. No release of histamine from guinea-pig lung was observed at this pH. At pH 8.2, histamine release occurred both from rat and guinea-pig lung, and was proportional to the logarithm of the concentration of compound 48/80.3. Histamine release from rat lung by 20 mug/ml. of 48/80 decreased when the pH was raised from 7.4 to 8.2; but the release caused by 1 mg/ml. of 48/80 increased both in rat and guinea-pig lung as the pH was raised.4. 2-4-Dinitrophenol (DNP) inhibited the release of histamine from rat lung by a concentration of 20 mug/ml. of 48/80; the inhibition was prevented by glucose. DNP did not affect histamine release from rat or guinea-pig lung by a concentration of 1 mg/ml. of 48/80 and enhanced the release when the pH was raised from 7.4 to 8.2.5. 1 mg/ml. of 48/80 did not inhibit the enhanced oxygen consumption produced by DNP in the isolated rat diaphragm.6. Iodoacetic acid (IAA) or a Ca/Mg-free medium inhibited the release of histamine by 20 mug/ml. of 48/80 from rat lung but not the release produced by 1 mg/ml. in either rat or guinea-pig lung.7. The degranulation of rat mesentery mast cells caused by 20 mug/ml. of compound 48/80 was inhibited by DNP. The degranulation evoked by 1 mg/ml. of 48/80 was also sensitive to this inhibitor; in this instance, however, the metachromatic staining reaction of the mesentery mast cells was greatly diminished.8. It is concluded that two processes of histamine release by compound 48/80 occur in rat lung. One, dependent on cell metabolism, involves, mast cell granule secretion. The other, independent of cell metabolism, seems to consist of a simple exchange reaction between histamine and compound 48/80, and this is the only one occurring in guinea-pig lung.     

The role of membrane bound sialic acid of rat mast cells in histamine release induced by compound 48/80 and derivatives as well as calcium

Histamine release induced by compound 48/80 from rat mast cells is not dependent on extracellular Ca2+. Preincubation of mast cells with trypsin has only little effects on histamine release induced by this polycation. This work also demonstrates that histamine release induced by compound 48/80 and its analogues in the absence of extracellular Ca2+ depends on membrane bound sialic acid of the mast cell. Neuraminidase treatment of the cells in the presence of extracellular Ca2+ leads to histamine liberation. These findings suggest that sialic acid residues of the mast cell membrane constitute the site at which polycations exert their stimulatory actions of histamine liberation.     

Calcium dependency of inhibition by arachidonic acid of compound 48/80-induced histamine release from mast cells

Compound 48/80 ( compd 48/80)-induced histamine secretion from rat mast cells was inhibited almost completely by pretreatment of the cells at 37 degrees with 25 microM arachidonic acid in the presence of 1.8 mM Ca2+. As the Ca2+ concentration was reduced below 1.8 mM, 25 microM arachidonic acid became less inhibitory and, then, progressively more stimulatory for histamine release with or without compd 48/80. No additive effect on histamine release was obtained by combining compd 48/80 and arachidonic acid. Pretreatment of mast cells with lidocaine, an inhibitor of Ca2+ binding to phospholipid, or with nordihydroguaiaretic acid, an inhibitor of Ca2+ flux and lipoxygenase, stimulated arachidonic acid-induced histamine release. Arachidonic acid also inhibited a compd 48/80-induced spike increment of intracellular 45Ca2+ uptake and a decrease of total 45Ca2+ uptake by 45Ca2+-preloaded mast cells. Arachidonic acid and Ca2+ also suppressed melittin-induced histamine release and compd 48/80-induced release of radioactivity from mast cells preloaded with [3H]arachidonic acid. These results suggest that exogenous arachidonic acid or its metabolite(s) may interact with membrane-associated Ca2+, disturbing Ca2+ availability for the trigger mechanism of compd 48/80-induced histamine release or inhibiting the subsequent metabolism of arachidonic acid via the lipoxygenase pathway to form active metabolites involved in the histamine liberating mechanism.     

Lack of histamine involvement in parathyroid hormone hypotensive action

Promethazine and cimetidine blocked the hypotensive actions of 2-pyridylethylamine, and H1 agonist and dimaprit, an H2 agonist, respectively, but not that of bovine parathyroid hormone fragment [bPTH-(1-34)]. Rats were treated repeatedly with the histamine releaser, compound 48/80, until the release could no longer produce a decrease in blood pressure. The hypotensive action of bPTH-(1-34) could still be seen. Rats with histamine partially depleted with one injection of compound 48/80 were injected with cimetidine and pyrilamine, and H1 antagonist, which together blocked the hypotensive action of subsequent injections of compound 48/80, but not that of bPTH-(1-34). These data suggest that the vasodilatory action of bPTH-(1-34) does not involve the release or action of histamine.     

Hypotension induced by growth-hormone-releasing peptide is mediated by mast cell serotonin release in the rat.

Growth-hormone-releasing peptide (GH-RP-6) is a synthetic hexapeptide that selectively releases growth hormone (GH) when administered to a number of animals species. In the rat, maximal GH release occurs after intravenous administration of 100 micrograms/kg GH-RP-6. Intravenous administration of 5 mg/kg GH-RP-6 produced 100% lethality within 2-5 min of drug administration. Further investigative studies demonstrated that the lethal effect of GH-RP-6 was preceded by an initial hypertensive episode, followed by a rapid, profound hypotension and bradycardia. The rise and fall in blood pressure also were observed in pithed rats treated with GH-RP-6, suggesting that the central nervous system was not responsible for the changes in blood pressure. However, the GH-RP-6-induced bradycardia was not observed in pithed rats, indicating the fall in heart rate was mediated through a central reflex mechanism. No direct effects of GH-RP-6 were seen in the isolated rat aorta or canine saphenous vein. Pretreatment of conscious rats with naloxone (10 mg/kg, iv), an opiate receptor antagonist, did not prevent the hypertensive response to GH-RP-6, but the hypotension and lethality were attenuated. Pretreatment with cyproheptadine (2.5 mg/kg, iv), a dual serotonin/histamine antagonist, or ketanserin (3 mg/kg, iv), a selective serotonin antagonist, prevented the GH-RP-6-induced hypotension and lethality. Cyproheptadine unmasked a 40 mm Hg rise in mean arterial pressure which persisted for over 10 min. In addition, degranulation of mast cells with compound 48/80 inhibited the toxicity of GH-RP-6, suggesting that mast cell degranulation and the subsequent release of autocoids is responsible for the cardiovascular effects of GH-RP-6. In vitro, GH-RP-6 (10(-5) - 10(-3) M) produced a concentration-related release of histamine from rat peritoneal mast cells. However, the histamine release by GH-RP-6 (10(-4) M) was not inhibited by naloxone (10(-4) M) in isolated mast cells, suggesting either that peritoneal mast cells are not responsible or that the mast cell degranulation in vitro is not opiate mediated. In conclusion, it appears that GH-RP-6 degranulates mast cells releasing serotonin, which produces hypotension, bradycardia, and death. This degranulation of mast cells is apparently inhibited by naloxone in vivo, suggesting that opiate receptors are involved in the hypotension and lethality associated with the administration of GH-RP-6.     

Blood histamine levels and arteriovenous concentration differences after the intravenous administration of the basic compounds l-3 and 48/80 in the anaesthetized dog.

The effects of the i.v. administration of inulin trinicotinate-monomethochloride (L-3) on haemodynamics, airway pressure and blood histamine levels were studied in chloralose-anaesthetized dogs and compared with the effects of compound 48/80. The control arterial histamine level was 0.041 plus or minus 0.002 mug/ml (mean plus or minus SEM) as determined by a fluorometric assay. L-3 (0.15 mg/kg) released high amounts of histamine, as indicated by a peak level in arterial histamine of 0.212 plus or minus 0.027 mug/ml within 3 min, which was not futher enhanced on increasing the dosage of L-3 to 1 mg/kg. After the i.v. injection of 0.15 mg/kg of 48/80 the peak level in arterial histamine was 0.146 plus or minus 0.008 mug/ml, and the level was further markedly elevated to 0.918 plus or minus 0.068 mug/ml after the administration of 1 mg/kg of 48/80. The concomitant fall in systemic blood pressure and the rise in airway pressure can be satisfactorily explained on the basis of histamine liberation. Whereas these parameters as well as the blood histamine concentration gradually returned to control values, the heart rate remained elevated during the observation period of 2 h. The arteriovenous differences in blood histamine across various tissues and organs following L-3 and 48/80 administration indicated histamine release mainly from skin and muscle and histamine uptake by the kidney, the digestive tract and to a lesser extent the lungs. The portal-hepatic vein differences revealed no consistent changes in liver histamine balance. As regards the lungs and liver, the present results suggest a dynamic equilibrium between histamine release and uptake in these organs in the intact animal. Both, L-3 and 48/80 elicited a similar pattern of histamine release and uptake. The extreme histamine releasing capacity of 1 mg/kg of 48/80 may be explained by an additional non-selective mechanism of histamine liberation.     

The lack of compound 48/80-induced contraction in isolated trachea of mast cell-deficient Ws/Ws rats in vitro: the role of connective tissue mast cells

In the rat trachea, two types of mast cells have been identified, connective tissue mast cells and mucosal mast cells. Their different characteristics may account for their different biological functions. The role of connective tissue mast cells in tracheal contraction as one feature of the immediate reaction of asthma was studied in vitro in isolated trachea, using tissue derived from mast cell-deficient (Ws/Ws) rats, heterozygous (Ws/+) rats and control (+/+) rats, and compound 48/80 as a potent inducer of mast cell degranulation. The contractile response of tracheas from the three types of rats was also studied upon exposure to the following spasmogens: histamine, 5-hydroxytryptamine (5-HT), and carbachol. Histamine content in tissues reflected the differing mast cell numbers in strips from the three rat types. It was found that carbachol and 5-HT elicited tracheal contraction in a similar manner in strips from the three types of rats. Histamine had no contractile effect. Compound 48/80, at a dose of 25 microg/ml, elicited contraction in tracheas from both control (+/+) and heterozygous (Ws/+), but not in trachea from Ws/Ws rats. Compound 48/80-induced contractions in tracheas from +/+ rats were inhibited by 0.1 microM ketanserin and 0.1 microM nedocromil, but not by 0.1 microM mepyramine. Enzyme histochemistry confirmed that the degranulation occurred in connective tissue mast cells, but not in mucosal mast cells. We concluded that connective tissue mast cells play an important role in rat tracheal contraction via 5-HT release induced by compound 48/80. In addition, the specific mast cell-deficient (Ws/Ws) rats provide a good tool for studying the roles of mast cells in airway system.     

Differential response of mast cells separated from various organs and basophils of dogs to the fluoroquinolone antimicrobial levofloxacin

Histamine releases induced by the fluoroquinolone antimicrobial levofloxacin (LVFX) were investigated using mast cells separated from various organs and peripheral basophils of dogs, being the most susceptible species to quinolone derivatives, in both in vivo and in vitro systems. An intravenous infusion of LVFX at 30 mg/kg over a 30-min period produced endogenous histamine release from 5 min, and a maximum at 30 min, in which the plasma LVFX concentration was approximately 50 microM. A close correlation (r = 0.87, n = 20) between histamine and LVFX concentrations in plasma during the infusion was observed. In the in vitro study, LVFX at 30 microM or more caused histamine release from mast cells separated from the liver and skin, but not from the gastric mucosa, lung, and peripheral basophils. More exactly, the liver mast cells were most susceptible to LVFX among the organs tested. On the other hand, compound 48/80, a prototype histamine liberator, elicited the histamine release from the liver or skin mast cells at 10 microg/ml, and the calcium ionophore A23187 at 1 microM exhibited the histamine release from the mast cells derived from all organs examined. Histochemical analysis revealed that the liver and skin mast cells had positive reaction for both alcian blue and safranin staining, but the gastric mucosa and lung mast cells were only positive for alcian blue staining, indicating that LVFX preferably activated the connective tissue-type mast cells rather than the mucosal-type mast cells. The degranulation of the liver and skin mast cells brought about by either LVFX or compound 48/80, unlike the calcium ionophore A23187, was blocked by pretreatment with pertussis toxin, suggesting the involvement of pertussis toxin-sensitive G proteins. The results obtained from the canine experiments strongly suggest that LVFX induces histamine release from the connective tissue-type mast cells distributed mainly in the liver, somewhat in the cutaneous tissue, through the activation of pertussis toxin-sensitive G proteins.     

THE HYPOTENSIVE RESPONSE TO COMPOUND 48/80 IN NORMOTENSIVE AND HYPERTENSIVE RATS

1. The administration of an initial dose of 50 micrograms/kg of 48/80 produced a sharp fall in the blood pressure of normotensive rats but produced little change in blood pressure in spontaneously hypertensive rats. 2. The administration of an additional 50 micrograms/kg and 100 micrograms/kh of 48/80 in normotensive and spontaneously hypertensive rats resulted in equivalent decreases in pressure in both groups. 3. Both groups had equivalent decreases in blood pressure in response to methylhistamine. 4. Spontaneously hypertensive rats appear to have a reduced ability to release histamine in response to 48/80 due to either an increased threshold for 48/80 or a diminished histamine storage pool.     

Comparison of histamine release from peritoneal mast cells derived from diabetic and control rats.

Clinical and experimental diabetes are associated with an increased number of mast cells and elevated tissue histamine concentrations. This study compared histamine release from peritoneal mast cells derived from diabetic and control rats. Experimental diabetes was induced by a single i.v. injection of streptozotocin (50 mg/kg body weight). Measurement of plasma glucose levels confirmed the diabetic state. Peritoneal mast cells were stimulated for 10 min with the lectin concanavalin A (0.5-100 micrograms/ml) in the presence or absence of phosphatidylserine, clinical dextran (0.6-1200 micrograms/ml) in the presence of phosphatidylserine, the calcium ionophore A23187 (0.1-1 microM) or the basic releasing agent compound 48/80 (0.1-10 micrograms/ml). Histamine release induced by these agents was similar in both populations. Further studies will compare the differences in histamine release from mast cells isolated from different tissues, e.g. heart and lung. In addition, physiological stimuli which are altered in the diabetic state (e.g. hyperosmolalar solutions and free radical generating systems) are under investigation.     

Cyclic AMP independent inhibition by papaverine of histamine release induced by compound 48/80.

Compound 48/80-induced histamine release from isolated rat peritoneal mast cells was inhibited in a dose-dependent manner by papaverine (ic₅₀ approx 20 μM). This effect of papaverine was not influenced by PGE₁ (14–140 μM), even though PGE₁ markedly increased must cell cAMP levels. Papaverine (0.5 mM) completely inhibited histamine release without causing any change in cAMP levels. Theophylline (0.1 and 0.5 mM) potentiated histamine release induced by submaximal concentrations of compound 48/80, while cAMP levels were increased. IBM X was as potent as papaverine in causing inhibition of mast cell phosphodiesterase. IBM X (0.14–0.7 mM) had no effect on histamine release but caused a 6–20 fold increase in mast cell cyclic AMP. Papaverine inhibition of histamine release was gradual at the onset and was parallelled by a depletion of mast cell ATP content. The inhibition of 48/80-induced histamine release and depletion of mast cell ATP levels was reversed by glucose. It is concluded that papaverine induced inhibition of 48/80-induced histamine release is independent of cAMP, is unrelated to phosphodiesterase inhibition but is dependent upon inhibition of energy production.     

Inhibition of mast cell disruption and histamine release in rat anaphylaxis in vitro. Comparison with compound 48/80

In vitro anaphylactic reaction causes mast cell damage and histamine release from rat tissue. Histamine release is correlated with mast cell damage and both phenomena are simultaneously inhibited by various metabolic inhibitors, antipyretics, calcium lack and previous heating of the tissue at 45°. The mast cell damage produced by antigen in sensitized rat tissues is morphologically similar to that caused by compound 48/80, both agents causing extrusion of granules. Mast cell damage and histamine release induced by antigen or by compound 48/80 are inhibited alike by several substances and conditions. It is suggested that in rats the histamine-releasing mechanism of the antigen-antibody reaction in anaphylaxis is very similar to that of compound 48/80.