In vitro studies on the mechanism of action of a new antiallergic,Ro 21-7634

The effects of Ro 21-7634 and disodium cromoglycate (cromoglycate) on the in vitro release of mediators of anaphylaxis from rat peritoneal cells and guinea pig lung tissue were compared. Ro 21-7634 was 25 fold more potent than cromoglycate as an inhibitor of antigen-induced histamine release from passively sensitized (IgE) rat peritoneal cells. Ro 21-7634 was also the more potent inhibitor of both compound 48/80- and concanavalin A-induced histamine release from rat peritoneal cells. The two drugs shared the common properties of producing the same maximal level of inhibition in each of the above releasing systems and exhibiting a time and concentration dependent loss of inhibitory activity when added to the cells prior to the releasing agent. Neither drug inhibited ionophore A23187- or ionophore X537A-induced histamine release from these cells. Ro 21-7634 inhibited antigen-induced (IgG₁) histamine and SRS-A release from actively sensitized guinea pig lung fragments, whereas cromoglycate did not. The results indicate that Ro 21-7634 and cromoglycate act through a common mechanism to inhibit allergic mediator release and that Ro 21-7634 is the more potent inhibitor.     

Ro 21-7634, a new antiallergic agent with potent oral activity

Ro 21-7634 was examined for oral antiallergic activity in two in vivo models commonly used to evaluate anti-allergics. In the rat PCA test, this drug had an oral ID₅₀ of 1.14 mg/kg and was found to be more potent than several other antiallergics including Disodium Cromoglycate (cromoglycate), Oxatomide, Doxanthrazole, Xanoxate, 2,6-bis (ethoxyoxalylamino) pyridine, PRD-92-EA and M+B 22,948. In contrast to cromoglycate, Ro 21-7634 was found to be an orally active inhibitor of antigen-induced bronchoconstriction in passively sensitized rats (ID₅₀=0.2 mg/kg). In addition, Ro 21-7634 inhibited antigen-induced histamine release in an in vivo passive peritoneal anaphylaxis test system, following intraperitoneal administration. Ro 21-7634 demonstrated no end organ antagonism toward histamine, methacholine or serotonin in the guinea pig.     

Pharmacologic regulation of antigen-induced mediator release from canine lung.

The ascaris antigen-induced release of histamine and a slow-reacting substance of anaphylaxis (SRS-A) from passively sensitized fragmented canine lung is further characterized. Histamine and SRS-A were released within 30 sec of antigen challenge, reached a maximum at 7 and 10 min, respectively, and thereafter appeared to remain constant to 30 min. Contractions of guinea pig ileum produced by canine SRS-A were competitively antagonized by the SRS-A antagonist FPL-55712. Indomethacin and deuterium oxide enhanced antigen-induced SRS-A release from canine lung but had little effect on histamine release. The ability of several chemically novel 'antiallergic agents' to inhibit mediator release was evaluated. Inhibition of histamine release, and to a lesser extent SRS-A release, by one of these compounds was shown to vary with time and temperature. It is concluded that fragmented canine lung, while disclosing some qualitative pharmacological differences from other species, is a useful in vitro model of immediate hypersensitivity reactions.     

Release of slow-reacting substance of anaphylaxis from dispersed pig lung cells: effect of cyclo-oxygenase and lipoxygenase inhibitors

Study of the release of slow-reacting substance of anaphylaxis (SRS-A).from lung cells has been hampered by the lack of a suitable animal model. Using both immunologic and pharmacologic stimuli, we have obtained histamine and SRS-A release from dispersed pig lung cells containing 6% mast cells (with a histamine content of 1.9 pglcell). Lung cells dispersed from actively sensitized (with intratracheal Ascaris antigen) but not unsensitized pigs released both histamine (mean net release 33%) and SRS-A (mean release, 47 units/10⁷ cells) when challenged with Ascaris antigen. Greater release of histamine (mean net release 52%) and of slow-reacting substance (SRS) (mean release 701 units/10⁷ cells) was induced by challenge with the calcium ionophore A23187. The pharmacologic and physicochemical characteristics of the SRS together with its profile of enzymatic inactivation resembled those described for SRS-A released from human lung. Both antigen-induced and A23187-induced SRS(-A) release were enhanced by indomethacin, a cyclo-oxygenase inhibitor, but inhibited by both phenidone (IC₅₀ 35 μM) and eicosatetraenoic acid (IC₅₀ 15 μM), inhibitors of both cyclo-oxygenase and lipoxygenase, confirming that generation of SRS(-A) by either stimulus required an intact lipoxygenase pathway of arachidonic acid metabolism.     

Inhibitory effect of econazole on the release of thromboxanes

The effect of econazole on the release of thromboxanes was investigated. It was found that econazole inhibited concentration-dependently the aggregation of guinea pig platelets stimulated with arachidonic acid. The compound also reduced significantly the LTB₄-induced contraction of guinea pig lung parenchyma strips and the contraction of rabbit aorta to the effluent of LTD₄-stimulated guinea pig lungs, both effects mediated mostly by thromboxane generation. The concentration of TXB₂ in the effluents from LTD₄ stimulated lungs, assayed by EIA, was significantly reduced following pretreatment of the lungs with 10^–4 M and 10^–5 M of econazole, whereas the levels of PGE₂ were increased. These results demonstrate that econazole is a selective inhibitor of thromboxane synthesis.     

Passive sensitization of guinea-pig skin in vitro for the antigen-induced release of anaphylactic mediators

Guinea-pig skin fragments were passively sensitized for the antigen-induced release of histamine, SRS-A and ECF-A. Skin histamine was chemically identified by fluorimetry; SRS-A gave a characteristic dose-dependent contraction of the guinea-pig ileum; and ECF-A selectively attracted eosinophils. The antibody mediating the release of these agents was shown to be IgG₁. Following antigen challenge different time courses of release were demonstrable for histamine, SRS-A and ECF-A. Skin SRS-A was resistant to treatment with the enzyme pronase and skin ECF-A had an estimated molecular size of between 500 and 1000. They were therefore comparable to similar agents released from the lung. Thus SRS-A and ECF-A join histamine as chemical mediators in cutaneous anaphylaxis.     

The guinea-pig lung strip: a study of the mediators of the Schultz-Dale reaction

A new in vitro preparation, the isolated lung strip of the guinea-pig, is described for investigating the Schultz-Dale reaction and the effect of drugs on the smooth muscles of the lung.Histamine caused a contraction of the preparation. This was reversed to a relaxation in the presence of the H1-blocker brompheniramine. The relaxation was blocked by the H2-blocker methiamide, indicating the presence of both H1- and H2-receptors. Brompheniramine, 10^–9–10^–5 M, delayed the onset and diminished the maximum Schultz-Dale contraction, whereas methiamide, 10^–4 M, increased the antigen-induced contraction without influencing the time of onset of the contraction.Diffusate from challenged and chopped guinea-pig lung contracted the lung strip. This was completely blocked by a combination of brompheniramine, 10^–5 M, and the SRS/A blocker FPL 55712, 10 g/ml. However, FPL 55712 did not influence either the onset or the extent of the Schultz-Dale contraction of the lung strip. Indomethacin, 0.05–5 g/ml, did not influence the Schultz-Dale contraction, whereas a high dose, 50 g/ml, decreased the height of the contraction.It is concluded that the isolated lung strip of the guinea-pig is a useful in vitro model for studying the Schultz-Dale reaction. The smooth muscles contain histamine receptors of H1 and H2 type. The anaphylactic contraction, especially during the early phase, is partially mediated by histamine. The lack of evidence of SRS-A as an important mediator depends more probably on the inability of FPL 55712 to block the effect of endogenously generated SRS-A than on the lack of SRS-A receptors on the smooth muscles of the lung.Subsidiary to AB Astra, Sweden.     

Thein vivo andin vitro activity of AHR-13268D,a new antiallergic/antihistaminic agent

AHR-13268D (4-[3-[4-[Bis(4-flurophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzoic acid, sodium salt) is a potent, long-acting water soluble, antiallergic and antihistaminic agent. AHR-13268D protects sensitive guinea pigs from collapse induced by aerosolized antigen; 1, 5, and 24 h ED₅₀s in the test were 0.27, 0.25, 0.93 mg/kg, PO, respectively. AHR-13268D was also active when given as an aerosol, the 1 h ED₅₀=0.29%. In the rat passivefoot anaphylaxis test, AHR-13268D was slightly more active (1.55 times) than AHR-5333B when given orally 1 h prior to challenge and equipotent to cromolyn when given intravenously immediately prior to challenge. AHR-13268D displayed potent, long-acting antihistaminic activity in naive guinea pigs; the 1, 5, and 24 h oral ED₅₀s being in the range of 0.3 mg/kg. AHR-13268D (10 to 20 mg/kg, PO) attenuated the skin responses to ascaris antigen in sensitive dogs and did not alter the EEG pattern or sleep/wake patterns of cats at doses in vast excess of its antihistaminic activity.In vitro, AHR-13268D was a potent inhibitor of histamine release from rat peritoneal mast cells (IC₅₀=0.51 nM) and was as potent as the reference 5-LO inhibitor phenidone in inhibiting antigen-induced contractions of guinea pig ileum in the presence of pyrilamine, atropine, and imidazole (IC₅₀300 M). AHR-13268B was bioavailable (88%) from capsules or from oral solutions.     

The pharmacological profile and initial clinical evaluation of tiacrilast (Ro 22-3747): a new antiallergic agent

Tiacrilast (Ro 22-3747) is an allergic mediator release inhibitor which has demonstrated potent oral activity in two IgE-mediated animal models of immediate hypersensitivity: the rat passive cutaneous anaphylaxis test (ID₅₀ of 0.65 mg/kg) and a model in which anaphylactic bronchospasm is induced in passively sensitized rats (ID₅₀ of 0.022 mg/kg). In addition to oral efficacy, in the latter model Ro 22-3747 was 23-fold more potent than cromoglycate by the aerosol (nebulization) route of administration.In vitro studies have confirmed that the mechanism of action of Ro 22-3747 in thein vivo models is through allergic mediator release inhibition since Ro 22-3747 was a potent inhibitor of antigen-induced (IgE-mediated) histamine release from passively sensitized rat peritoneal cellsin vitro (IC₅₀ values of 0.25 and 1.5 M for Ro 22-3747 and cromoglycate, respectively), and Ro 22-3747 did not display end organ antagonism to histamine, serotonin, or the leukotrienes. Clinical evaluations of Ro 22-3747 at a 350 mg oral dose have been conducted in patients with allergic asthma and allergic rhinitis. In a limited study in allergic asthmatics, Ro 22-3747 demonstrated significant inhibitory activity relative to placebo in reducing acute airway responses to inhaled pollen extracts in patients with ragweed sensitivity (measured by changes in log PD₂₀ FEV₁ and log PD₃₅ SGaw). The activity seen, however, was less than that observed with cromoglycate (20 mg) administered by inhalation. In a pilot evaluation in patients with allergic rhinitis, Ro 22-3747 administered at a 350 mg oral dose exhibited activity significantly greater than placebo in terms of improvements in the objective measurement of changes in nasal airflow at 2 and 3 hrs after treatment and the subjective overall global evaluation made by the patients at the end of the treatment period. The preclinical pharmacology and initial clinical efficacy of Ro 22-3747 support the continued clinical evaluation of this drug for prophylactic use in the management of asthma and other allergic disorders.     

β-Endorphin modulates anaphylactic contractions of tracheae isolated from actively sensitized guinea pigs

It has been shown that opioid peptides induce histamine release and enhance antigen-induced histamine release from isolated peritoneal mast cells. Little is known about the effect of opioid peptides on mast cells present in airway smooth muscle. In the present study, the effect of-endorphin on antigen-induced contractions of isolated tracheal rings from actively sensitized guinea pigs was studied. It appears that-endorphin has a bidirectional effect on anaphylactic contractions of the trachea. Low concentrations of-endorphin (0.1 and 10 nM) significantly potentiate the anaphylactic contractions of tracheal rings. In contrast, higher concentrations of-endorphin (0.1 and 1 M) significantly suppress the anaphylactic contractions of guinea pig trachea. In the presence of the non-selective opioid receptor antagonist naloxone, 10 nM of-endorphin still potentiates the anaphylactic contractions of the trachea. This demonstrates that the potentiation of anaphylactic contractions of guinea pig trachea by low concentrations of-endorphin is not mediated by opioid receptors. We speculate that the potentiation of the anaphylactic contraction by-endorphin is due to an interaction with mast cells.     

Anaphylatoxin-induced shock and two patterns of anaphylactic shock: Hemodynamics and mediators*

In the dog, différent cardiorespiratory reactions were identified in two types of anaphylactic shock and in C5a-AT (anaphylatoxin)-induced shock. AU three types had in common a portai blood pooling with conséquent decrease in the venous return, cardiac output, and arterial pressure. In anaphylaxis (a) of the first type, at a low titer of hemagglutinating antibodies, the latent period was 68 s and heart and lung function was unchanged. In the second type, at high titer, the latency was 19 s and pulmonary hypertension and decreased heart contractility occurred. After AT injection pulmonary hypertension appeared with tachypnea and unchanged heart function. Tachyphylaxis, but not cross-over tachyphylaxis against the anaphylactic agent and AT was observed in dogs and isolated guinea pig lungs. AT induced a tran-sient release and a. a prolonged release of histamine, prostaglandins (PGs), and thromboxane A₂ and endoperoxides from guinea pig lungs. SRS-A was released only in a. Indomethacin inhibited AT-induced release of PGs in guinea-pig lungs and AT-induced hypotension in the dog though it did not prevent the drop in cardiac output. Thèse model studies suggest that différent patterns of clinical a. can occur, depending on the type of antibodies and/or mediators involved.     

Guinea pig eosinophil major basic protein (GMBP) as a potent histamine releaser. (I) Histamine releasing activity of GMBP and its chemical structure

When isolated guinea pig major basic protein (MBP) was applied to SDS-PAGE, it exhibited a single band with an apparent molecular weight of 11000. When rat peritoneal mast cells were exposed to MBP at concentrations higher than 0.3 M, significant histamine release was elicited both in the presence and absence of extracellular Ca²⁺. The histamine releasing activity of MBP was more pronounced in a Ca-free medium than in the presence of Ca²⁺. When MBP was applied on reverse phase HPLC, two distinct peaks were observed. These two proteins exhibited identical molecular weights and pI values. Their amino acid compositions were very similar. It was therefore assumed that guinea pig MBP is composed of two subtypes, namely GMBP₁ and GMBP₂, and that both have similar histamine releasing activities. MBP elicited not only⁴⁵Ca uptake from the extracellular medium but also induced Ca²⁺ release from intracellular Ca stores.     

Effect of inhibition of arachidonic acid metabolism on anaphylaxis of guinea pig lung strips

The effect of inhibitors of the cyclooxygenase and/or lipoxygenase pathways of arachidonic acid metabolism on the anaphylactic contraction of lung parenchymal strips from ovalbumin sensitized guinea pigs was studied. Indomethacin, a selective cyclooxygenase inhibitor, significantly enhanced the anaphylactic contraction at 10^–6 M with no effect at 10^–5 or 10^–4 M. By contrast, nordihydroguaiaretic acid (NDGA, 10^–5 and 10^–4 M), a lipoxygenase inhibitor, and 1-phenyl-3-pyrazolidinone (phenidone, 10^–4 M), an inhibitor of both the cyclooxygenase and lipoxygenase markedly inhibited the anaphylactic contractile response. The pattern of inhibition was similar to that produced by FPL 55712, an antagonist of slow reacting substance of anaphylaxis (SRS-A), and was characterized by a decrease in the maximum tension and in the duration of the contraction. The results suggest that inhibition of the lipoxygenase pathway reduced anaphylactic contraction of guinea pig lung strips possibly by inhibiting the synthesis and release of SRS-A.     

BRL 22321, a compound that has mast cell stabilizing activity similar to that of disodium cromoglycate and in addition has smooth muscle relaxing activity

BRL 22321 is 4,9-dihydro-6,7-dimethyl-4,9-dioxo-1H-naphtho[2,3-d]-v-triazole sodium salt. It combines some of the chemical structural features of disodium cromoglycate (DSCG) and theophylline. It has mast cell stabilizing activity similar to that DSCG and in addition it has some smooth muscle relaxant activity. BRL 22321 was more potent than DSCG as an inhibitor of rat passive cutaneous and peritoneal anaphylaxis (PCA and PPA) and histamine release by antigen from passively sensitized rat peritoneal cellsin vitro. In the rat PCA test it was active when given orally and a large intravenous dose of DSCG reduced the potency of subsequent intravenous doses of either DSCG or BRL 22321, suggesting that the compounds were active by a common pathway. The compounds had similar potencies as inhibitors of the release, by antigen, of histamine and slow reacting substance of anaphylaxis (SRS-A) from passively sensitized human lung fragments. BRL 22321 was more potent than DSCG and theophylline as an inhibitor of a cyclic adenosine and a cyclic guanosine monophosphate phosphodiesterase. BRL 22321 inhibited histamine release in systems in which DSCG was inactive, for example it inhibited histamine release by antigen from chopped lung taken from hyperimmune guinea pigs and by anti-IgE from human leucocytes; in these tests it was more potent than theophylline. BRL 22321 had smooth muscle relaxant activity not shown by DSCG. It relaxed histamine elevated tone in guinea pig lung strip and tracheal spiral preparations at doses at which theophylline produced a dose dependent response. It was difficult to compare potencies since there was a difference in the nature of the responses to the drugs. DSCG had little activity over the same dose range or at higher doses. BRL 22321 also reduced increased airways resistance in the anaesthetized guinea pig produced by 5-hydroxytryptamine (5-HT) or histamine but at somewhat higher doses than those at which theophylline was active. BRL 22321 was not an antagonist of acetylcholine, histamine, 5-HT or SRS-A on the isolated guinea pig ileum.     

Pharmacological investigations into the effects of histamine and histamine analogs on guinea pig and rat uterus

The effects of histamine and its analogs 2-(2-pyridyl) ethylamine (PEA) and 4-methylhistamine (4 MH) have been studied on uterine preparations obtained from estrogenprimed guinea pigs and rats.

1. Histamine and 4 MH, a specific H₂-receptor agonist produced relaxation in estrogen-primed rat uterus, whereas these agonists produced contraction in the estrogenprimed guinea pig uterus.
2. PEA, a specific H₁-receptor agonist produced contraction in the guinea pig uterus but had no effect on the rat uterus.
3. Metiamide blocked responses to histamine and 4 MH in the rat uterus, whereas mepyramine blocked responses to histamine and PEA in the guinea pig uterus.
4. Propranolol produced competitive antagonism with histamine in the rat uterus, whereas it had no significant effect on the histamine or PEA responses in the guinea pig uterus.
5. Reserpine pretreatment completely abolished the responses to histamine and 4 MH in the rat uterus but did not alter the responses in the guinea pig uterus.
6. Our data suggest that in rat uterus only H₂-receptors are present and they act indirectly through the release of noradrenaline. In the guinea pig uterus both H₁-and H₂-receptors are present and are excitatory and directly acting.

     

Mechanism of the action of amoxanox (AA-673), an orally active antiallergic agent

Amoxanox inhibited immunologically stimulated and LTD4-induced bronchoconstriction in laboratory animals. Amoxanox, like DSCG, inhibited rat IgE-mediated PCA and histamine release from rat peritoneal mast cells, and suppressed immunologically stimulated or calcium ionophore A23187-induced SRS-A generation in rat peritoneal cavity and guinea pig lung fragments. This compound also reduced the contractile response of guinea pig lung parenchymal and ileal strips to LTD4, but did not significantly affect the response of the ileum to either histamine or acetylcholine. Therefore, the antiallergic action of amoxanox seems to be associated with inhibition of chemical mediator release and antagonistic activity on SRS-A.     

The influence of a new corticosteroid,budesonide, on anaphylactic bronchoconstriction and SRS-A release in the guinea pig

Groups of guinea pigs sensitized with ovaibumin were treated with budesonide and beclomethasone dipropionate, respectively, in an intraperitoneal dose of 50 mg/kg. 20 h later, the anaphylactic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from chopped lung tissue was studied. Whereas the corticosteroids studied had no effect on the tissue content of histamine or on the amount of antigen-induced release of this autacoid, budesonide and beclomethasone dipropionate to a great extent inhibited the release of SRS-A. The anti-anaphylactic effect of budesonide and beclomethasone was also shown in sensitized guinea pigs pretreated with mepyramine, 2.5 mg/kg intraperitoneally, and challenged with nebulized ovalbumin. We suggest that the partial protection given by the corticosteroids budesonide and beclomethasone dipropionate is due to the inhibition of SRS-A release.Subsidiary of AB Astra, Sweden.     

The inhibition of 5-lipoxygenase by RG 6866

The generation of leukotrienes C₄, D₄ and E₄ from arachidonic acid is dependent upon the activity of 5-lipoxygenase (5-LOX). The effects of RG 6866 (N-methyl-4-benzyloxyphenylacetohydroxamic acid) on the activity of guinea pig 5-LOXin vitro andin vivo were determined in the present study. The generation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) from arachidonic acid by isolated guinea pig peritoneal polymorphonuclear (PMN) cells was inhibited by incubation with RG 6866 (IC₅₀=0.20 M). A similar effect (IC₅₀=0.23 M) was observed when 5-HETE production was measured in a supernatant fraction from PMNs. Additionally, the compound did not inhibit³H-LTD₄ binding to guinea pig membranes. In actively sensitized guinea pigs pretreated with indomethacin, propranolol and pyrilamine, RG 6866 inhibited antigen-induced systemic anaphylaxis and LTD₄-dependent bronchoconstriction in a dose-dependent manner following oral administration. In the pulmonary anaphylaxis model, significant (p<0.05) inhibition of the mortality was observed within 30 min and maintained through four hours after treatment with RG 6866 (50 mg/kg i.g.). Finally, orally administered RG 6866 inhibited the formation of LTC₄ in these animals with an ED₅₀=24.0 mg/kg. These findings indicate that RG 6866 is an inhibitor of 5-LOX bothin vitro andin vivo.Previously designated as REV-6866 in a preliminary communication.     

Inhibition of antigen-induced contraction of guinea pig isolated tracheal muscle with 2-n-butyl-3-dimethylamino-5,6-methylenedioxy indene (MDI-A), indane (MDI-B) and 8-(diethylamino)octyl-3,4,5-trimethoxy benzoate hydrochloride (TMB-8)

The effects of three intracellular calcium antagonists on antigen-induced contraction of sensitized guinea pig tracheal muscle were investigated. The agents employed were: 2-n-butyl-3-dimethylamino-5,6-methylenedioxy indene hydrochloride (MDI-A), 2-n-butyl-3-dimethylamino-5,6-methylenedioxy indane hydrochloride (MDI-B) and 8-(diethylamino)octyl-3,4,5-trimethoxy benzoate hydrochloride (TMB-8). Each of these agents caused a concentration-dependent inhibition of the antigen-induced contraction of sensitized tracheal smooth muscle. Moreover, in histamine and leukotriene D4 (LTD4) incited contractions of guinea pig tracheal muscle, they showed antagonistic action. The induced tracheal muscle contraction, achieved through the addition of compound 48/80 to a solution of ethylene glycol bis (beta-aminoethylether)-N,N,N1, N1-tetraacetic acid (EGTA) in a contained Ca-free medium, was completely inhibited by individual pretreatment with MDI-A, MDI-B and TMB-8. In the case of tracheal muscle contraction induced by CaCl2 in a high potassium, Ca-free medium, only TMB-8 inhibited contraction. Lastly, none of these three intracellular calcium antagonists affected the antigen-induced release of histamine and slow reacting substance of anaphylaxis (SRS-A). These results suggest that MDI-A and MDI-B inhibit the antigen-induced contraction of sensitized guinea pig tracheal muscle by interfering with the contractile responses caused by histamine and LTD4.     

Nitric oxide modulates cardiac and mast cell anaphylaxis

Anaphylaxis in the isolated guinea-pig heart was associated with a sudden release of histamine with a long-lasting release of nitrite (NO ⁻₂ ), an oxidation product of NO.N ^G-monomethyl-l-arginine (MeArg, 300 μM) increased the severity of cardiac anaphylaxis, as shown by the decrease in the coronary flow and by a prolonged duration of antigen-induced arrhythmias. Concomitantly, MeArg increased the release of histamine while decreasing the release of nitrite. Sodium nitroprusside (NaNP, 10⁻⁵–10⁻⁴ M) reduced the severity of cardiac anaphylaxis by increasing coronary flow and shortening the duration of antigen-induced arrhythmias. Concomitantly, NaNP decreased the release of histamine while increasing the release of nitrite. In mast cells isolated from actively sensitized guinea-pigs, the release of histamine elicited by specific antigen was increased by MeArg and decreased by NaNP.

In conclusion, endogenous and exogenous NO antagonizes the effect of vasoconstrictor mediators released after antigen challenge and plays a protective role in anaphylactic reactions “in vitro”,