Q:

10/7/2013
A 23 year-old male had a life threatening rxn to an allergy shot, very low dose, and had just taken 2 tablets of the supplement L arginine 30 min prior. Reports say this could have caused more hypotension and wheeze, what do you know about this supplement and do other supplements do the same thing? Should patients be told not to take these meds while on immunotherapy?

A:

Thank you for your inquiry.

This question brings up a number of very complex issues about which we have a great deal of information, but even with such information, we cannot give you a definitive answer to your final question which is the advisability of patients receiving immunotherapy not using supplements of L-arginine.

L-arginine has many effects on the body. The most relevant pertinent to our discussion is its ability to induce the synthesis of nitric oxide. When one looks at these physiologic effects, one can see that they can be both potentially beneficial as well as detrimental during an episode of anaphylaxis. Potentially beneficial are the effects of nitric oxide on the lung (where it is a bronchial smooth muscle dilator) and on the mast cell (where it can prevent degranulation). However, it has a potentially detrimental effect on shock since it is a very potent peripheral vasodilator. It appears as if this is the most salient effect, and therefore, overall, nitric oxide should have a deleterious effect on the outcome of anaphylactic shock. This has been confirmed by experiments in animals and also by the effects of treatment to block nitric oxide synthesis in humans experiencing anaphylactic episodes ) see abstracts below). Perhaps the most salient reference for you in this regard is the reference from the Annals of Allergy (see below). All of the other effects are also documented in the references and abstracts copied below for your convenience.

However, studying the pharmacodynamics of the ingestion of 6 grams of L-arginine, it was found that it would be highly doubtful that a significant effect would occur within an hour. This would not, however, rule out the possibility of a steady state effect induced by daily ingestion of such a supplement, but I could find no reference that evaluated this issue.

Thus, in summary, based upon an overview of the available literature, the use of L-arginine as a supplement, via the enhanced production of nitric oxide, could clearly have a detrimental effect, worsening hypotension occurring during anaphylactic shock (but not increasing bronchoconstriction). It is unclear, however, whether a single ingestion of such a supplement would have a rapid enough onset as well as a significant enough effect to worsen the outcome of an event occurring during immunotherapy.Thus, there is no definitive answer, at least of which I am aware, as to the need to inhibit L-arginine supplements in patients on immunotherapy, but there is at least theoretical evidence that the ingestion of such substances could adversely affect hypotension occurring during an anaphylactic episode.

As noted, the abstracts below are the basis for this answer, and you might find the article in the Annalshelpful in further reviewing this issue.

Thank you again for your inquiry and we hope this response is helpful to you.

Med Sci Monit. 2003 Nov;9(11):CS102-6.
Methylene blue: an effective treatment for contrast medium-induced anaphylaxis.
Oliveira Neto AM, Duarte NM, Vicente WV, Viaro F, Evora PR.
Source
Prodiagnóstico--Sao Gonçalo, RJ, Brazil.
Abstract
Background: The purpose of this paper is to propose methylene blue as a lifesaving alternative drug for the treatment of contrast-induced anaphylaxis.
Case Report: In a cardiovascular catheterization laboratory invasive hemodynamic monitoring was used to document the lifesaving effect of IV bolus injections of 1.5-2 mg/Kg methylene blue solution to treat three patients for anaphylactic shock following radiocontrast injection during coronary angiography. Methylene blue administration was followed by prompt circulatory improvement, leading to hemodynamic stabilization and relief of other anaphylactic symptoms in each case. There were no deaths.
Conclusions: Our findings suggest that methylene blue can be lifesaving in anaphylactic shock, notwithstanding some transitory side effects, such as cardiac rhythm disturbances and chest pain, both of which possibly originate from sudden myocardial perfusion deficits.

Sao Paulo Med J. 2007 Jan 4;125(1):60-2.
Methylene blue for clinical anaphylaxis treatment: a case report.
Rodrigues JM, Pazin Filho A, Rodrigues AJ, Vicente WV, Evora PR.
Source
Department of Surgery and Anatomy, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, CEP 14015-120, Brazil.
Abstract
Context and Objective: Nitric oxide has a pathophysiological role in modulating systemic changes associated with anaphylaxis. Nitric oxide synthase inhibitors may exacerbate bronchospasm in anaphylaxis and worsen clinical conditions, with limited roles in anaphylactic shock treatment. The aim here was to report an anaphylaxis case (not anaphylactic shock), reversed by methylene blue (MB), a guanylyl cyclase inhibitor.
Case Report: A 23-year-old female suddenly presented urticaria and pruritus, initially on her face and arms, then over her whole body. Oral antihistamine was administered initially, but without improvement in symptoms and signs until intravenous methylprednisolone 500 mg. Recurrence occurred after two hours, plus vomiting. Associated upper respiratory distress, pulmonary sibilance, laryngeal stridor and facial angioedema (including erythema and lip edema) marked the evolution. At sites with severe pruritus, petechial lesions were observed. The clinical situation worsened, with dyspnea, tachypnea, peroral cyanosis, laryngeal edema with severe expiratory dyspnea and deepening unconsciousness. Conventional treatment was ineffective. Intubation and ventilatory support were then considered, because of severe hypoventilation. But, before doing that, based on our previous experience, 1.5 mg/kg (120 mg) bolus of 4% MB was infused, followed by one hour of continuous infusion of another 120 mg diluted in dextrose 5% in water. Following the initial intravenous MB dose, the clinical situation reversed completely in less than 20 minutes, thereby avoiding tracheal intubation.
Conclusion: Although the nitric oxide hypothesis for MB effectiveness discussed here remains unproven, our intention was to share our accumulated cohort experience, which strongly suggests MB is a lifesaving treatment for anaphylactic shock and/or anaphylaxis and other vasoplegic conditions.

Ann Allergy Asthma Immunol. 2007 Oct;99(4):306-13.
Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue.
Evora PR, Simon MR.
Source
Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Abstract
Objective: To review the role of nitric oxide production in anaphylaxis.
Data Sources: We performed MEDLINE searches of the literature. In addition, some references known to the authors but not listed in MEDLINE, such as abstracts and a CD-ROM, were included. Finally, additional clinical details of the cases were provided by one of the authors.
Study Selection: Primary reports were preferentially selected for inclusion. However, some secondary publications are also cited.
Results: Histamine along with other mediators, such as leukotrienes, tumor necrosis factor, and platelet-activating factor, induce the production of nitric oxide. Nitric oxide can inhibit the release and effects of catecholamines. Sympathetic amines may inhibit production of nitric oxide. Studies in animals have demonstrated the generation of nitric oxide during anaphylaxis. Inhibition of nitric oxide synthase improves survival in an animal model of anaphylaxis. Nitric oxide causes vasodilation indirectly by increasing the activation of guanylyl cyclase, which then causes smooth muscle relaxation by increasing the concentration of smooth muscle cyclic guanosine monophosphate. Methylene blue is an inhibitor of guanylyl cyclase, which increases systemic vascular resistance and reverses shock in animal studies. The previously reported successful treatment with methylene blue of 11 patients with anaphylactic hypotension is reviewed.
Conclusion: Nitric oxide plays a significant role in the pathophysiology of anaphylaxis. Treatment with methylene blue should be considered in patients with anaphylactic hypotension that has not responded to other interventions.

AANA J. 2008 Aug;76(4):271-4.
Methylene blue for refractory hypotension: a case report.
Weissgerber AJ.
Source
Naval Medical Center, San Diego, California, USA.
Abstract
Methylene blue has multiple indications for use, but recently it has been shown to be useful in treating refractory hypotension. Anaphylaxis results in widespread vasodilation and hypotension. Epinephrine has been described as the drug of choice in the treatment of hypotension for anaphylaxis, but the increased heart rate may be poorly tolerated by some patients. This case report describes a 79-year-old man with a history of diastolic dysfunction who was admitted for elective coronary artery bypass graft surgery. After induction of general anesthesia, symptoms of anaphylaxis developed with urticaria and decreased mean arterial pressure. The hypotension was refractory to vasoactive agents and volume repletion. Methylene blue was primed in the cardiopulmonary bypass pump and was effective in restoring hemodynamic stability. Furthermore, the patient required a decreased amount of vasoactive agents in the postoperative course. The suspected mechanism of action of methylene blue is inhibition of the enzyme nitric oxide synthase, which ultimately prevents the smooth muscle dilation that accompanies anaphylaxis. Methylene blue may be a valuable adjunct in the treatment of anaphylaxis and other causes of refractory hypotension.

An inhibitor of nitric oxide production, NGnitro-L-arginine-methyl ester, improves survival in anaphylactic shock
European Journal of Pharmacology
Volume 203, Issue 1, 2 October 1991, Pages 125–127
Abstract
Induction of anaphylactic shock in mice by i.v. antigen challenge (bovine serum albumin, 100 mg) or i.v. treatment with the mast cell degranulator compound 48/80 resulted in 80 and 90% mortality rate, respectively. Inhibition of nitric oxide (NO) synthesis from L-arginine by co-injection of the L-arginine analog NGnitro-L-arginine methyl ester (L-NAME, 30 mg/kg) reduced the mortality rate by 40 and 20% in the antigen- and compound 48/80-induced shock models. Treatment with 60 mg/kg L-NAME reduced the mortality rate by 60% in these shock models. This beneficial effect was reversed by addition of L-arginine (120 mg/kg) but not D-arginine (120 mg/kg). These results suggest NO production as a possible mechanism involved in the pathophysiology of anaphylactic shock.

Eur J Pharmacol. 1991 Oct 2;203(1):125-7.
An inhibitor of nitric oxide production, NG-nitro-L-arginine-methyl ester, improves survival in anaphylactic shock.
Amir S, English AM.
Source
Centre for Studies in Behavioral Neurobiology, Concordia University, Montreal, Canada.
Abstract
Induction of anaphylactic shock in mice by i.v. antigen challenge (bovine serum albumin, 100 micrograms) or i.v. treatment with the mast cell degranulator compound 48/80 resulted in 80 and 90% mortality rate, respectively. Inhibition of nitric oxide (NO) synthesis from L-arginine by co-injection of the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg) reduced the mortality rate by 40 and 20% in the antigen- and compound 48/80-induced shock models. Treatment with 60 mg/kg L-NAME reduced the mortality rate by 60% in these shock models. This beneficial effect was reversed by addition of L-arginine (120 mg/kg) but not D-arginine (120 mg/kg). These results suggest NO production as a possible mechanism involved in the pathophysiology of anaphylactic shock.

J Gen Physiol. 2010 Mar;135(3):247-59. doi: 10.1085/jgp.200910365.
Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations.
Perez-Zoghbi JF, Bai Y, Sanderson MJ.
Source
Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Abstract
Nitric oxide (NO) induces airway smooth muscle cell (SMC) relaxation, but the underlying mechanism is not well understood. Consequently, we investigated the effects of NO on airway SMC contraction, Ca(2+) signaling, and Ca(2+) sensitivity in mouse lung slices with phase-contrast and confocal microscopy. Airways that were contracted in response to the agonist 5-hydroxytryptamine (5-HT) transiently relaxed in response to the NO donor, NOC-5. This NO-induced relaxation was enhanced by zaprinast or vardenafil, two selective inhibitors of cGMP-specific phosphodiesterase-5, but blocked by ODQ, an inhibitor of soluble guanylyl cyclase, and by Rp-8-pCPT-cGMPS, an inhibitor of protein kinase G (PKG). Simultaneous measurements of airway caliber and SMC [Ca(2+)](i) revealed that airway contraction induced by 5-HT correlated with the occurrence of Ca(2+) oscillations in the airway SMCs. Airway relaxation induced by NOC-5 was accompanied by a decrease in the frequency of these Ca(2+) oscillations. The cGMP analogues and selective PKG activators 8Br-cGMP and 8pCPT-cGMP also induced airway relaxation and decreased the frequency of the Ca(2+) oscillations. NOC-5 inhibited the increase of [Ca(2+)](i) and contraction induced by the photolytic release of inositol 1,4,5-trisphosphate (IP(3)) in airway SMCs. The effect of NO on the Ca(2+) sensitivity of the airway SMCs was examined in lung slices permeabilized to Ca(2+) by treatment with caffeine and ryanodine. Neither NOC-5 nor 8pCPT-cGMP induced relaxation in agonist-contracted Ca(2+)-permeabilized airways. Consequently, we conclude that NO, acting via the cGMP-PKG pathway, induced airway SMC relaxation by predominately inhibiting the release of Ca(2+) via the IP(3) receptor to decrease the frequency of agonist-induced Ca(2+) oscillations.

J Immunol. 1997 Aug 1;159(3):1444-50.
Nitric oxide inhibits IgE-mediated degranulation of mast cells and is the principal intermediate in IFN-gamma-induced suppression of exocytosis.
Eastmond NC, Banks EM, Coleman JW.
Source
Department of Pharmacology and Therapeutics, University of Liverpool, United Kingdom.
Abstract
IFN-gamma regulates various aspects of rodent peritoneal mast cell function, including mediator release, cell growth, TNF-alpha-mediated cytotoxicity, and MHC class II expression. We investigated whether the suppressive action of IFN-gamma on IgE/Ag-mediated degranulation of mast cells is mediated via synthesis of nitric oxide. Incubation of mouse peritoneal cells with L-NMMA, an inhibitor of nitric oxide synthase, or in medium lacking the nitric oxide precursor L-arginine reversed the inhibitory effect of IFN-gamma on Ag-induced serotonin release. Furthermore, the nitric oxide donors sodium nitroprusside and S-nitrosoglutathione inhibited degranulation, and this effect was direct, since it was seen equally on purified and unfractionated mast cells and occurred independently of IFN-gammaR expression. Additional experiments revealed that accessory cells in peritoneal cell populations were the principal target for the action of IFN-gamma and the main source of nitric oxide; the cytokine was more potent on unfractionated compared with purified mast cells, and IFN-gamma induced detectable nitrite production in mixed peritoneal cells, but not in purified mast cells. These studies show that IFN-gamma induces nitric oxide production in peritoneal cell populations, and that synthesized nitric oxide directly inhibits the IgE-mediated secretory function of mast cells. The activation of nitric oxide-producing cells in the tissue microenvironment may be important in the control of mast cell-dependent allergic reactions.

Nutr Metab (Lond). 2012 Jun 12;9(1):54. doi: 10.1186/1743-7075-9-54.
Acute L-Arginine supplementation does not increase nitric oxide production in healthy subjects.
Alvares TS, Conte-Junior CA, Silva JT, Paschoalin VM.
Source
Laboratory of Advanced Analysis in Biochemistry and Molecular Biology, Department of Biochemistry, Chemistry Institute, Federal University of Rio de Janeiro, Brazil.
Abstract
Dietary supplements containing L-arginine have been marketed with the purpose of increasing vasodilatation, and thus, blood and oxygen supply to the exercising muscle. The present study evaluated the acute effect of L-arginine supplementation on indicators of NO production, nitrite (NO2-) + nitrate (NO3-) (NOx), in healthy subjects. Plasma concentrations of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have also been addressed. Seventeen healthy males participated in a randomized, double-blind, placebo-controlled study. Blood samples were drawn from a left antecubital vein at baseline (T0). Afterwards, subjects were randomly submittedto 6 g of oral L-arginine supplementation (as L-arginine hydrochloride) or placebo (as corn starch); afterwards, the subjects remained at rest in supine position and blood samples were drawn again at 30 (T1), 60 (T2), 90 (T3) and 120 minutes (T4) after supplementation. To analyze NO production, NO3- was converted to NO2- by nitrate reductase, followed by the derivatization of NO2- with 2,3-diaminonaphthalene. NOx, ADMA and SDMA were analyzed using a high-performance liquid chromatography system and monitored with a fluorescence detector. Two-way ANOVA with repeated measures showed no significant changes in NOx concentrations on the L-arginine group as compared to placebo group at any of the fivetime points (T0: 17.6 ± 3.9 vs 14.6 ± 2.3 μmol/L; T1: 15.8 ± 2.4 vs 14.3 ± 1.7 μmol/L; T2: 16.8 ± 4.9 vs 13.7 ± 2.7 μmol/L; T3: 16.7 ± 3.9 vs 14.6 ± 2.1 μmol/L; T4: 15.1 ± 2.8 vs 13.5 ± 3.5 μmol/L). Furthermore, plasma levels of ADMA and SDMA were not statistically significant between the L-arginine and placebo groups at T0 (0.43 ± 0.19 vs 0.39 ± 0.15 μmol/L and 1.83 ± 1.13 vs 1.70 ± 0.62 μmol/L), respectively. In conclusion, acute L-arginine supplementation does not increase plasma concentration of NOx in healthy individuals with normal plasma concentrations of ADMA.

Rolla, et al:Level of exhaled nitric oxide during human anaphylaxis Annals of Allergy, Asthma & Immunology
Volume 97, Issue 2 , Pages 264-265, 1 August 2006
Background: Nitric oxide (NO) seems to play an important pathophysiologic role in modulating the systemic changes associated with anaphylaxis. Even if some effects of NO may be protective, animal models of anaphylaxis have shown that the summation effects of NO are deleterious, resulting in hypotension and loss of intravascular volume. There are no studies of NO production during anaphylaxis in humans.
Objectives: To measure the level of exhaled NO during anaphylaxis induced by bee venom cluster immunotherapy in a 34-year-old beekeeper.
Methods: Exhaled NO was measured using a chemiluminescence analyzer at different flow rates, and alveolar NO concentration and airway NO production were calculated.
Results: We measured a high level of exhaled NO (78 ppb at 50 mL/s, with increased alveolar concentration and airway production) during anaphylaxis induced by bee venom immunotherapy in this patient. Normal values of exhaled NO were measured in the same patient 1 week later before and after a modified regimen of desensitization.
Conclusions: Nitric oxide production was increased in the respiratory tract during anaphylaxis. Having excluded all the common causes of increased exhaled NO levels, these results support the hypothesis that NO plays an important role in anaphylaxis.

Eur J Pharmacol. 1991 Oct 2;203(1):125-7.
An inhibitor of nitric oxide production, NG-nitro-L-arginine-methyl ester, improves survival in anaphylactic shock.
Amir S, English AM.
Source
Centre for Studies in Behavioral Neurobiology, Concordia University, Montreal, Canada.
Abstract
Induction of anaphylactic shock in mice by i.v. antigen challenge (bovine serum albumin, 100 micrograms) or i.v. treatment with the mast cell degranulator compound 48/80 resulted in 80 and 90% mortality rate, respectively. Inhibition of nitric oxide (NO) synthesis from L-arginine by co-injection of the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg) reduced the mortality rate by 40 and 20% in the antigen- and compound 48/80-induced shock models. Treatment with 60 mg/kg L-NAME reduced the mortality rate by 60% in these shock models. This beneficial effect was reversed by addition of L-arginine (120 mg/kg) but not D-arginine (120 mg/kg). These results suggest NO production as a possible mechanism involved in the pathophysiology of anaphylactic shock.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology