Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue

Review

Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue Paulo R. B. Evora, MD, PhD* and Michael R. Simon, MD†

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. Ann Allergy Asthma Immunol. 2007;99:306–313.

INTRODUCTION Anaphylaxis is a clinical syndrome that results from the effects of the release of mast cell and basophil mediators.1 This release usually occurs after antigenic stimulation of mast cells in people who have been previously sensitized and have responded with an IgE response to the antigen. In other situations anaphylaxis may be induced by physical stimuli, complement activation, or direct chemical-induced mast cell activation or may be idiopathic. Clinical features of anaphylaxis include signs and symptoms referable to the upper and lower respiratory tracts, the gastrointestinal and genitourinary tracts, the skin, the eye, and, importantly, the cardiovascular system. Life-threatening episodes typically involve the respiratory tract and the cardiovascular system. Cardiovascular

* Department of Surgery and Anatomy, Ribeira˜o Preto Faculty of Medicine, University of Sa˜o Paulo, Ribeira˜o Preto, Sa˜o Paulo, Brazil. † Division of Allergy and Clinical Immunology, Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, and Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine, Detroit, Michigan. Authors have nothing to disclose. Received for publication February 20, 2007. Received in revised form May 22, 2007. Accepted for publication May 24, 2007.

306

manifestations include tachycardia and hypotension. Mast cell and basophil mediators cause vasodilation and increased vascular permeability, which results in decreased effective intravascular volume, leading to hypotension. Decreased systemic vascular resistance has been documented in human anaphylaxis.2– 4 The purpose of this article is to review the evidence for the production of nitric oxide in anaphylaxis and its possible role in the cardiovascular manifestations of anaphylaxis. Furthermore, the effects of the administration of methylene blue, which interferes with the physiologic effect of nitric oxide on smooth muscle, are presented as a case series derived from published sources. We performed MEDLINE searches of the literature. Primary reports were preferentially selected for inclusion. However, some secondary publications are also cited. 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. MEDIATORS OF ANAPHYLAXIS AND NITRIC OXIDE PRODUCTION Histamine Histamine is the mediator that is believed to play the most significant role in the origin of the cardiovascular manifesta-

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

tions of anaphylaxis.5 In dogs, both right atrial histamine administration and antigen-induced anaphylaxis caused acute severe circulatory failure because of sequestration of blood in the splanchnic vasculature.6 Histaminic effects on the cardiovascular system in humans are mediated by both histamine1 (H1)- and H2-receptors.7–14 Histamine causes H1-receptor– mediated arterial contraction15,16 and vasodilation16,17 and H2receptor–mediated relaxation, which is dependent on the presence of an intact endothelium.18 One of the mechanisms by which histamine may affect the vasculature involves nitric oxide (Figure 1). Nitric oxide causes vasodilation indirectly by increasing the activation of guanylyl cyclase, which then increases the concentration of smooth muscle cyclic guanosine monophosphate (cGMP).19,20 cGMP, in turn, causes relaxation of vascular smooth muscle.19 Early experiments in rats,21,22 dogs,23 and human pulmonary arteries24 have demonstrated that the ability of histamine to cause arterial vasodilation is dependent on an intact vascular endothelium. Because endothelial nitric oxide synthase

is an endothelial enzyme, this suggests a role for endothelial cell nitric oxide production in histamine-induced vasodilation. Histamine-induced vasodilation in mice is partially dependent on the presence of endothelial nitric oxide synthase.25 Histamine up-regulates endothelial nitric oxide synthase gene expression26 and induces the production of nitric oxide in porcine aortic27 and human umbilical vein endothelial cells.28,29 Inhibition of nitric oxide synthase decreases histamine-induced vasodilation in feline mesentery30 and hind limbs,31 porcine coronary venules,32 monkey cerebral arteries,33 and human ophthalmic arteries.34 In addition, evidence in a hamster model indicates that a histamine-induced increase in vascular permeability is decreased by the inhibition of nitric oxide synthase.35 Inhibition of guanylate cyclase reduces histamine-induced vasodilation in cats31 and blocks histamine-induced permeability in pig coronary venules.32 These data strongly suggest that histamine induces the production of nitric oxide and that histamine-induced vasodilation is partly mediated by nitric oxide and cGMP. Other Mast Cell Mediators Leukotrienes,1 platelet-activating factor (PAF),36,37 tumor necrosis factor (TNF),38 and other mediators may also contribute to the anaphylactic syndrome. Leukotriene-induced relaxation of splanchnic venous capacitance vessels in dogs is dependent on an intact endothelium.39 In this system, inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl ester and inhibition of guanylate cyclase with methylene blue blocks this effect of leukotrienes. PAF-induced relaxation of rat aorta is dependent on endothelial production of cGMP and is prevented by inhibition of nitric oxide synthase.40 Inhibition of nitric oxide synthase results in complete recovery from PAF-induced shock in dogs.41 In a mouse model, PAF induces hypotension and death by induction of endothelial nitric oxide synthase.42 Activated mast cells release TNF.38 TNF is capable of activating nitric oxide synthase, with the resulting generation of increased amounts of nitric oxide.43,44 Finally, a recent commentary45 suggests that nitric oxide produced by inducible nitric oxide synthase in mast cells46 may trigger production of other inflammatory mediators, such as prostaglandin E2.45

Figure 1. Endothelial cell receptors are linked to the intracellular production and release of nitric oxide (NO) by G proteins (GP). GP are required for the transduction of the signal between cell membrane receptors and the cell signaling mechanisms. The endothelial cell mechanism of NO synthesis includes phospholipase C (PLC) activation and production of inositol triphosphate (IP3) from phosphatidyl inositol 4,5-biphosphate (PIP2). IP3 promotes cytosolic Ca2⫹ release. Constitutive endothelial NO synthase (eNOS) is activated by this Ca2⫹ increase combining with calmodulin. eNOS produces NO from its substrate L-arginine. NO stimulates guanylate cyclase in adjacent smooth muscle cells, which causes an increase in cyclic guanosine monophosphate (cGMP) levels. cGMP is the final stimulus that causes vasorelaxation. Methylene blue inhibits the activity of guanylate cyclase, with a resulting decrease in the production of cGMP and less vascular smooth muscle relaxation.

VOLUME 99, OCTOBER, 2007

NITRIC OXIDE GENERATION IN ANAPHYLAXIS Murine Models Biochemical and animal studies suggest that nitric oxide is an anaphylactic mediator. The first study to suggest a role for nitric oxide in anaphylactic shock in animals demonstrated that administration before anaphylaxis of an inhibitor of nitric oxide synthase, NG-nitro-L-arginine-methyl ester, resulted in improved survival in mice.47 The participation of nitric oxide in mouse anaphylaxis was again suggested by attenuation of anaphylactic hypotension by administration of NG-nitro-Larginine-methyl ester.48 In both of these mouse studies, the effects of NG-nitro-L-arginine-methyl ester were counteracted

307

by administration of L-arginine, which is the substrate of nitric oxide synthase (Figure 1). Using the mouse model of anaphylaxis cited herein, Cauwels et al42 suggest that PAF is the major mediator in mouse anaphylaxis, because inhibition of PI3K (with wortmanin) and inhibition of protein kinase B (Akt) protects against antigen-induced anaphylactic hypothermia and death. PI3K and protein kinase B phosphorylate endothelial nitric oxide synthase and thereby increase nitric oxide production. Hypotension was inhibited by blocking nitric oxide synthase activity with N␻-nitro-L-arginine methyl ester and also by inhibition of PI3K and protein kinase B (Akt). Inhibition of guanylyl cyclase with methylene blue was partially protective in this model. This study clearly demonstrated the importance of endothelial nitric oxide synthase in murine anaphylaxis Rabbit Models Direct measurement of tissue nitric oxide using a nitric oxide–sensitive electrode placed between the abdominal fascia and the rectus abdominis fascia in rabbit anaphylaxis demonstrated increases in nitric oxide concentrations that varied in individual animals from undetectable to 0.7 ␮M at prechallenge measurements to between 5 and 19 ␮M after antigen challenge.49 However, other investigators could not detect changes in plasma nitrate in a compound 48/80 model of rabbit anaphylaxis.50 The inability to demonstrate increased plasma nitrate in these latter experiments may be because compound 48/80 does not activate all types of mast cells.51 Rabbit lung and liver mast cells52 and human lung tryptasetype mast cells51 are not activated by compound 48/80. However, compound 48/80 activates mast cells that contain both tryptase and chymase.51 In contrast, antigen-induced activation occurs in all mast cells that have been sensitized with antigen-specific surface IgE. Thus, experiments that involve antigen-induced activation of larger numbers of mast cells might have resulted in measurable concentrations of nitric oxide, whereas compound 48/80 activation of smaller numbers of mast cells does not. It is also possible that increases in nitric oxide production are detectable in tissue but not in plasma. In addition, the former research team then demonstrated that inhibition of nitric oxide synthase with N␻-nitroL-arginine methyl ester in their rabbit model of antigeninduced anaphylaxis decreases survival.53 These investigators suggest that the increased mortality was due to worsened bronchospasm and more severe depression in cardiac function.53 This may have been because N␻-nitro-L-arginine methyl ester inhibits nitric oxide production and diminishes nitric oxide–induced smooth muscle relaxation. The drug may thereby worsen bronchospasm and coronary artery constriction. Diminished ventricular blood flow may then have worsened contractility. However, venous return was improved with inhibition of nitric oxide synthase N␻-nitro-Larginine methyl ester,53 which results in less vasodilatation and peripheral pooling of blood.

308

Canine Model Protamine-induced canine anaphylactoid vasodilation is inhibited by NG-monomethyl-L-arginine, a competitive antagonist of nitric oxide synthase, and by methylene blue, an inhibitor of guanylyl cyclase,54,55 which suggests a role for nitric oxide in this protamine effect. Hypotension in a dog model of Ascaris suum antigen anaphylaxis was attenuated by N␻-nitro-L-arginine-methyl ester.56 Administration of N␻-nitro-L-arginine-methyl ester prevented decreased right atrial pressure and hemoconcentration, suggesting that increased vasopermeability was prevented. N␻-nitro-L-arginine-methyl ester administration was associated with a decrease in ventricular contractility (maximum change in ventricular pressure/time [dP/dtmax]) when dP/dtmax was normalized for mean arterial pressure to correct for changes in afterload.56 However, cardiac output was not changed by N␻-nitro-L-argininemethyl ester. Two of 5 control animals and none of 6 animals that received N␻-nitro-L-arginine-methyl ester died by 90 minutes after antigen challenge. These investigators next evaluated the production of nitric oxide in the canine anaphylactic heart in vivo using a nitric oxide–selective electrode.57 A suum antigen was administered systemically to induce anaphylaxis in 7 dogs. The nitric oxide electrode was placed on the surface of the left ventricle adjacent to the paraconal interventricular groove. Group data showed that the nitric oxide concentration increased significantly during the period from 2 to 3 minutes after antigen exposure. However, each animal manifested a unique temporal pattern. In 4 of them, nitric oxide concentrations peaked at 20 minutes. In 2 animals, the peak occurred at 30 to 35 minutes. Peak nitric oxide concentrations ranged from 0.25 to 8 ␮M.57 Human Reports In a single case report of human anaphylaxis, increased nitric oxide has been detected in exhaled breath.58 However, a retrospective study of patients with acute allergic reactions that included tachycardia and/or hypotension did not demonstrate serum nitric oxide concentrations that differed from those of subjects without those findings.59 Nitric oxide concentrations correlated with respiratory rate. A trend was seen toward correlation between nitric oxide concentrations and pulse pressure. This report in a non–peer-reviewed online journal presented only statistical group results. Group means, standard deviations, and data on individual patients were not reported. It is possible that there were individuals in whom serum nitric oxide was increased despite the fact that the group results did not reveal a difference. Nevertheless, from these measurements in humans and from the studies in rabbits, it appears that nitric oxide is produced in anaphylaxis but is measurable only in tissue but not in blood. A possible explanation for this observation is that plasma nitrate measurements underestimate total body nitric oxide production by 4- to 6-fold.60

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

Table 1. Summary of the Experience With Methylene Blue in the Treatment of Anaphylaxis Patient No./ sex/age, y

Clinical presentation

Cause of anaphylaxis

Minimal systolic blood pressure, mm Hg

Time to onset of action, min

1/F/56

Circulatory collapse, increased airway resistance

Protamine

2/F/16

Shock

Iodinated dye

3/M/26

Anaphylaxis without shock Shock

Penicillin

50

80-mg bolus, then Immediate 100-mg continuous infusion for 45 min 1.5-mg/kg bolus, then 1.5-mg/kg infusion 1.5-mg/kg infusion

Iodinated dye

20

1.5-mg/kg infusion

Iodinated dye

40

1.5-mg/kg bolus

⬍20

Post percutaneous transcoronary angioplasty (iodinated dye?) Iodinated dye

40

2.0-mg/kg bolus, then 2.0-mg/kg infusion

10

4/M 5/F/56

6/F/48

7/M/53

8/M/55

9/F/46

10/F/23

11/M/53

Glottal and facial edema and bronchospasm without shock Shock

Glottal edema, bronchospasm, hypotension Hypotension and hypoxemia

Iodinated dye

Shock with Penicillin cardiopulmonary arrest Pruritus, urticaria, Idiopathic vomiting, stridor, facial and lip angioedema, rales, shortness of breath, decreased consciousness Lingual and glottal Dipyrone edema, flushing, bronchospasm, cyanosis, bradycardia

Pulseless electrical activity

Methylene blue dosage

Reference(s)

Epinephrine, norepinephrine, fluids, open chest cardiac massage

76

Epinephrine, corticosteroid

77

Epinephrine, corticosteroid Epinephrine, corticosteroid Epinephrine, corticosteroid

77

Epinephrine, dopamine, corticosteroid

1.5-mg/kg infusion Almost Corticosteroid immediate 2.0-mg/kg bolus, then 2.0-mg/kg infusion Cardiac arrest 2.0-mg/kg bolus

1.5-mg/kg bolus, then 1.5-mg/kg infusion

Cardiac arrest 100-mg infusion for 5 min, repeated once

RELATIONSHIP OF HOMEOSTATIC AND THERAPEUTIC VASOPRESSORS TO NITRIC OXIDE The physiologic response to decreased effective circulating blood volume in anaphylaxis involves the release of endogenous catecholamines.4 Epinephrine is indicated for the initial treatment of anaphylaxis.1 Vasopressin61 and glucagon62 have

VOLUME 99, OCTOBER, 2007

10–15

Other medications used

15

Epinephrine, dopamine, corticosteroid Stable at 30 Crystalloid, colloid, epinephrine, corticosteroid ⬍20 H1-antihistamine methylprednisolone, epinephrine

Immediate

Epinephrine, atropine, succinylcholine, aminophylline dopamine, lidocaine, crystalloid, polyamide, cardioversion

77 78, 79

78, 79

78, 79

79

79

80

81

been advocated as adjunctive treatment for anaphylaxis in patients who have not responded to epinephrine. Glucagon inhibits production of inducible nitric oxide synthase and nitric oxide.63 Catecholamines activate adenyl cyclase, which results in increased cyclic adenosine monophosphate (cAMP).64 Vasopressin65 and glucagon64 also cause increases in cAMP. In turn, cAMP inhibits inducible nitric oxide syn-

309

thase and nitric oxide production.66,67 Nitric oxide, in turn, decreases release of catecholamines68,69 and the biological activity of norepinephrine.70 Nitric oxide synthase inhibition also increases catecholamine release.68 This suggests a homeostatic feedback mechanism between agonists that maintain vascular tone and nitric oxide. These agonists inhibit nitric oxide production. Nitric oxide inhibits the release and activity of catecholamines. The physiologic outcome depends on which effect is predominant. Intervention to inhibit the effect of nitric oxide would result in the catecholamine effects predominating. Anaphylactic hypotension is treated with fluid resuscitation, epinephrine, and other vasopressors if necessary. However, some patients with anaphylaxis do not respond to H1and H2-antihistamines along with fluid resuscitation, adrenergic agonists, and corticosteroids.71 Even with optimal medical management, anaphylactic hypotension may persist for many hours.71,72 Such lack of improvement suggests that current treatments do not correct all the pathophysiological events associated with anaphylactic hypotension and that other mediators may play an important role in this clinical syndrome. TREATMENT OF ANAPHYLAXIS BY INHIBITION OF GUANYLYL CYCLASE Animal Studies Successful use of methylene blue in various forms of vasodilatory circulatory shock suggests that reduction of cGMP production by inhibition of guanylyl cyclase is clinically attainable (Figure 1).73–75 A study of compound 48/80 –induced anaphylactic shock in rabbits documents that methylene blue prolongs survival and improves mean arterial blood pressure.50 A companion study of compound 48/80 –induced anaphylactic shock in pigs demonstrated that methylene blue increased systemic vascular resistance.76 However, in neither of these studies was there a documented difference in plasma nitrate concentrations between the control and experimental groups of animals. Clinical Experience Eleven patients with anaphylactic hypotension have been successfully treated with methylene blue.76 – 81 Table 1 summarizes the experience with methylene blue. Effective dosages ranged from a 1.5- to 2.0-mg/kg bolus and/or infusion. The clinical responses occurred within 20 minutes. This case series suggests that methylene blue is effective in reversing anaphylactic hypotension. Methylene blue has also been successfully used to treat 1 additional patient with protamineinduced anaphylactoid hypotension82 and 1 with aprotinin anaphylaxis.83 Methylene Blue Pharmacologic studies in sheep have shown that the 24-hour median lethal dose of methylene blue is 42.3 mg/kg (95% confidence interval, 37.3– 47.9 mg/kg) in that species.84 Experimental doses of 2.0 and 3.0 mg/kg in pigs and rabbits

310

resulted in no changes in mean arterial pressure in either species.76,85 The terminal half-life of methylene blue in healthy people is 5.25 hours.86 Reported toxic effects include hemolytic anemia in neonates at doses of 2 to 4 mg/kg; nausea, vomiting, abdominal pain, fever, and hemolysis at 7 mg/kg; and hypotension at 20 mg/kg.87,88 Methylene blue has also been reported to cause methemoglobinemia.89 –91 In humans, methylene blue is used at a dose of 5 to 7.5 mg/kg during parathyroid surgery to visualize the parathyroid glands.92–97 This dose is usually well tolerated. However, occasional transient neurotoxicity at these higher doses has been reported.98 –100 In Great Britain, the National Poisons Information Service recommends that the intravenous dose be 4 mg/kg or less.99 Physicians should also be aware that methylene blue interferes with pulse oximetry and causes the spurious appearance of oxygen desaturation.101,102 CONCLUSION Nitric oxide production in tissues has been documented in studies of anaphylaxis. The physiologic activities of the mediators of anaphylaxis can be partially attributed to the actions of nitric oxide. There appears to be a homeostatic feedback between nitric oxide and the agonists that maintain vascular tone. A case series is presented that suggests that methylene blue, which interferes with nitric oxide–induced smooth muscle relaxation, may be effective in the treatment of anaphylactic hypotension. We believe that treatment with methylene blue at a dose of 1 to 2 mg/kg should be considered in patients with anaphylactic hypotension that has not responded to other interventions. REFERENCES 1. Lieberman PL. Anaphylaxis and anaphylactoid reactions. In: Adkinson NF Jr, Yuninger JW, Busse WW, Bochner BS, Holgate ST, Simons FER, eds. Allergy Principles and Practice. 6th ed. Philadelphia, PA: Mosby; 2003:1497–1522. 2. Fahmy NR. Hemodynamics, plasma histamine, and catecholamine concentrations during an anaphylactoid reaction to morphine. Anesthesiology. 1981;55:329 –331. 3. Nicolas F, Villers D, Blanloeil Y. Hemodynamic pattern in anaphylactic shock with cardiac arrest. Crit Care Med. 1984; 12:144 –145. 4. Moss J, Fahmy NR, Sunder N, Beaven MA. Hormonal and hemodynamic profile of an anaphylactic reaction in man. Circulation. 1981;63:210 –213. 5. Winbery SL, Lieberman PL. Histamine and antihistamines in anaphylaxis. Clin Allergy Immunol. 2002;17:287–317. 6. Enjeti S, Bleecker ER, Smith PL, Rabson J, Permutt S, Traystman RJ. Hemodynamic mechanisms in anaphylaxis. Circ Shock. 1983;11:297–309. 7. Lorenz W, Doenicke A, Dittmann I, Hug P, Schwarz B. Anaphylaktoide reaktionen nach Applikation von Blutersatzmitteln beim Menschen Verhinderung dieser Nebenwirkung von Hemaccel durch Pramedikation mit H1- und H2 -Rezeptorantagonisten [Anaphylactoid reactions following administration of plasma substitutes in man: prevention of this sideeffect of Hemaccel by premedication with H1- and H2 -receptor antagonists]. Anaesthesist. 1977;26:644 – 648.

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

8. Philbin DM, Moss J, Akins CW, Rosow CE, Kono K, Schneider RC, VerLee TR, Savarese JJ. The use of H1 and H2 histamine antagonists with morphine anesthesia: a doubleblind study. Anesthesiology. 1981;55:292–296. 9. Kaliner M, Sigler R, Summers R, Shelhamer JH. Effects of infused histamine: analysis of the effects of H-1 and H-2 histamine receptor antagonists on cardiovascular and pulmonary responses. J Allergy Clin Immunol. 1981;68:365–371. 10. Lorenz W, Doenicke A, Schoning B, Ohmann C, Grote B, Neugebauer E. Definition and classification of the histaminerelease response to drugs in anesthesia and surgery: studies in the conscious human subject. Klin Wochenschr. 1982;60: 896 –913. 11. Kaliner M, Shelhamer JH, Ottesen EA. Effects of infused histamine: correlation of plasma histamine levels and symptoms. J Allergy Clin Immunol. 1982;69:283–289. 12. Owen DA, Harvey CA, Boyce MJ. Effects of histamine on the circulatory system. Klin Wochenschr. 1982;60:972–977. 13. Tryba M, Zevounou F, Zenz M. Prophylaxe anaphylakoider Reaktionen mit Promethazin und Cimetidin bei intramuskularer Applikation. Untersuchungun am Histamininfusions – Model [Prevention of anaphylactoid reactions using intramuscular promethazine and cimetidine studies of a histamine infusion model]. Anaesthesist. 1984;33:218 –223. 14. Dachman WD, Bedarida G, Blaschke TF, Hoffman BB. Histamine-induced venodilation in human beings involves both H1 and H2 receptor subtypes. J Allergy Clin Immunol. 1994; 93:606 – 614. 15. Shi W, Wang CG, Dandurand RJ, Eidelman DH, Michel RP. Differential responses of pulmonary arteries and veins to histamine and 5-HT in lung explants of guinea-pigs. Br J Pharmacol. 1998;123:1525–1532. 16. Daneshmand MA, Keller RS, Canver MC, Canver AC, Canver CC. Histamine H1 and H2 receptor-mediated vasoreactivity of human internal thoracic and radial arteries. Surgery. 2004;136: 458 – 463. 17. Lockwood JM, Wilkins BW, Halliwill JR. H1 receptormediated vasodilatation contributes to postexercise hypotension. J Physiol. 2005;563(pt 2):633– 642. 18. Lau WH, Kwan YW, Au AL, Cheung WH. An in vitro study of histamine on the pulmonary artery of the Wistar-Kyoto and spontaneously hypertensive rats. Eur J Pharmacol. 2003;470: 45–55. 19. Kawada T, Ishibashi T, Sasage H, Kato K, Imai S. Modification by LY83583 and methylene blue of relaxation induced by nitric oxide, glyceryl trinitrate, sodium nitroprusside and atriopeptin in aorta of the rat, guinea-pig and rabbit. Gen Pharmacol. 1994;25:1361–1371. 20. Friebe A, Koesling D. Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res. 2003;93:96 –105. 21. Van de Voorde J, Leusen I. Role of the endothelium in the vasodilator response of rat thoracic aorta to histamine. Eur J Pharmacol. 1983;87:113–120. 22. Krstic MK, Stepanovic RM, Krstic SK, Katusic ZS. Endothelium-dependent relaxation of the rat renal artery caused by activation of histamine H1-receptors. Pharmacology. 1989;38: 113–120. 23. Toda N. Endothelium-dependent relaxation induced by angiotensin II and histamine in isolated arteries of dog. Br J Pharmacol. 1984;81:301–307. 24. Ortiz JL, Labat C, Norel X, Gorenne I, Verley J, Brink C.

VOLUME 99, OCTOBER, 2007

25.

26.

27.

28.

29.

30. 31. 32.

33.

34. 35. 36. 37.

38.

39.

Histamine receptors on human isolated pulmonary arterial muscle preparations: effects of endothelial cell removal and nitric oxide inhibitors. J Pharmacol Exp Ther. 1992;260: 762–776. Payne GW, Madri JA, Sessa WC, Segal SS. Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/- mice. Am J Physiol Heart Circ Physiol. 2003;285:H493–H498. Li H, Burkhardt C, Heinrich UR, Brausch I, Xia N, Forstermann U. Histamine upregulates gene expression of endothelial nitric oxide synthase in human vascular endothelial cells. Circulation. 2003;107:2348 –2354. Kishi F, Nakaya Y, Takahashi A, Miyoshi H, Nomura M, Saito K. Intracellular and extracellular Ca2⫹ regulate histamineinduced release of nitric oxide in vascular endothelial cells as shown with sensitive and selective nitric oxide electrodes. Pharmacol Res. 1996;33:123–126. Rosenkranz-Weiss P, Sessa WC, Milstien S, Kaufman S, Watson CA, Pober JS. Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells: elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest. 1994;93:2236 –2243. Lantoine F, Iouzalen L, Devynck MA, Millanvoye-Van Brussel E, David-Dufilho M. Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2⫹ influx. Biochem J. 1998;330(pt 2):695– 699. Champion HC, Kadowitz PJ. R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat. Eur J Pharmacol. 1998;343:209 –216. Champion HC, Kadowitz PJ. NO release and the opening of K⫹ATP channels mediate vasodilator responses to histamine in the cat. Am J Physiol. 1997;273(2 pt 2):H928 –H937. Yuan Y, Granger HJ, Zawieja DC, DeFily DV, Chilian WM. Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. Am J Physiol. 1993;264(5 pt 2):H1734 –H1739. Ayajiki K, Okamura T, Toda N. Involvement of nitric oxide in endothelium-dependent, phasic relaxation caused by histamine in monkey cerebral arteries. Jpn J Pharmacol. 1992;60: 357–362. Haefliger IO, Flammer J, Luscher TF. Nitric oxide and endothelin-1 are important regulators of human ophthalmic artery. Invest Ophthalmol Vis Sci. 1992;33:2340 –2343. Mayhan WG. Nitric oxide accounts for histamine-induced increases in macromolecular extravasation. Am J Physiol. 1994;266(6 pt 2):H2369 –H2373. Choi IW, Kim YS, Kim DK, et al. Platelet-activating factormediated NF-kappaB dependency of a late anaphylactic reaction. J Exp Med. 2003;198:145–151. Finkelman FD, Rothenberg ME, Brandt EB, Morris SC, Strait RT. Molecular mechanisms of anaphylaxis: lessons from studies with murine models. J Allergy Clin Immunol. 2005;115: 449 – 457. Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF. Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci USA. 1991;88: 4220 – 4224. Pawloski JR, Chapnick BM. Leukotrienes C4 and D4 are potent endothelium-dependent relaxing agents in canine

311

40.

41. 42. 43.

44. 45. 46. 47. 48. 49. 50.

51.

52.

53.

54. 55.

56.

312

splanchnic venous capacitance vessels. Circ Res. 1993;73: 395– 404. Moritoki H, Hisayama T, Takeuchi S, Miyano H, Kondoh W. Involvement of nitric oxide pathway in the PAF-induced relaxation of rat thoracic aorta. Br J Pharmacol. 1992;107: 196 –201. Takekoshi K, Kasai K, Suzuki Y, et al. Effect of NG-nitro-Larginine on shock induced by endotoxin and by platelet activating factor in dogs. Eur J Pharmacol. 1993;250:465– 467. Cauwels A, Janssen B, Buys E, Sips P, Brouckaert P. Anaphylactic shock depends on PI3K and eNOS-derived NO. J Clin Invest. 2006;116:2244 –2251. Thiemermann C, Wu C-C, Szabo C, Perretti M, Vane JR. Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. Br J Pharmacol. 1993;110:177–182. Fahey TJ 3rd, Yoshioka T, Shires GT, Fantini GA. The role of tumor necrosis factor and nitric oxide in the acute cardiovascular response to endotoxin. Ann Surg. 1996;223:63– 69. Lowenstein CJ, Michel T. What’s in a name? eNOS and anaphylactic shock. J Clin Invest. 2006;116:2075–2078. Gilchrist M, McCauley SD, Befus AD. Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production. Blood. 2004;104:462– 469. Amir S, English AM. An inhibitor of nitric oxide production NG-nitro-L-arginine-methyl ester, improves survival in anaphylactic shock. Eur J Pharmacol. 1991;203:125–127. Osada S, Ichiki H, Oku H, Ishiguro K, Kunitomo M, Semma M. Participation of nitric oxide in mouse anaphylactic hypotension. Eur J Pharmacol. 1994;252:347–350. Mitsuhata H, Saitoh J, Takeuchi H, Hasome N, Horiguchi Y, Shimizu R. Production of nitric oxide in anaphylaxis in rabbits. Shock. 1994;2:381–384. Buzato MA, Viaro F, Piccinato CE, Evora PRB. The use of methylene blue in the treatment of anaphylactic shock induced by compound 48/80: experimental studies in rabbits. Shock. 2005;23:582–587. Oskeritzian CA, Zhao W, Min HK, Xia HZ, Pozez A, Kiev J, Schwartz LB. Surface CD88 functionally distinguishes the MCTC from the MCT type of human lung mast cell. J Allergy Clin Immunol. 2005;115:1162–1168. Ennis M, Lorenz W, Gerland W, Heise J. Isolation of mast cells from rabbit lung and liver: comparison of histamine release induced by the hypnotics Althesin and propanidid. Agents Actions. 1987;20:219 –222. Mitsuhata H, Saito J, Hasome N, Takeuchi H, Horiguchi Y, Shimizu R. Nitric oxide inhibition is detrimental to cardiac function and promotes bronchospasms in anaphylaxis in rabbits. Shock. 1995;4:143–148. Evora PR, Pearson PJ, Schaff HV. Protamine induces endothelium-dependent vasodilatation of the pulmonary artery. Ann Thorac Surg. 1995;60:405– 410. Raikar GV, Hisamochi K, Raikar BL, Schaff HV. Nitric oxide inhibition attenuates systemic hypotension produced by protamine. J Thorac Cardiovasc Surg. 1996;111:1240 –1246; discussion 1246 –1247. Mitsuhata H, Takeuchi H, Saito J, Hasome N, Horiguchi Y, Shimizu R. An inhibitor of nitric oxide synthase, N␻-nitro-Larginine-methyl ester, attenuates hypotension but does not improve cardiac depression in anaphylaxis in dogs. Shock. 1995;3:447– 453.

57. Saitoh J, Mitsuhata H, Takeuchi H, Hasome N, Shimizu R. In vivo production of nitric oxide in the canine heart in IgEmediated anaphylaxis. Shock. 1996;6:66 –70. 58. Rolla G, Nebiolo F, Guida G, Heffler E, Bommarito L, Bergia R. Level of exhaled nitric oxide during human anaphylaxis. Ann Allergy Asthma Immunol. 2006;97:264 –265. 59. Gupta A, Lin RY, Pesola GR, et al. Nitric oxide levels in patients with acute allergic reactions. Internet J Asthma Allergy Immunol. 2004;3:1. 60. Zeballos GA, Bernstein RD, Thompson CI, et al. Pharmacodynamics of plasma nitrate/nitrite as an indication of nitric oxide formation in conscious dogs. Circulation. 1995;91: 2982–2988. 61. Schummer W, Schummer C, Wippermann J, Fuchs J. Anaphylactic shock: is vasopressin the drug of choice? Anesthesiology. 2004;101:1025–1027. 62. Zaloga GP, Delacey W, Holmboe E, Chernow B. Glucagon reversal of hypotension in a case of anaphylactoid shock. Ann Intern Med. 1986;105:65– 66. 63. Harbrecht BG, Wirant EM, Kim YM, Billiar TR. Glucagon inhibits hepatocyte nitric oxide synthesis. Arch Surg. 1996; 131:1266 –1272. 64. Cell-to-cell signaling: hormones and receptors. In: Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J, eds. Molecular Cell Biology. New York, NY: WH Freeman & Co; 2000:chap 20. 65. Morello JP, Salahpour A, Laperriere A, et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest. 2000; 105:887– 895. 66. Smith FS, Ceppi ED, Titheradge MA. Inhibition of cytokineinduced inducible nitric oxide synthase expression by glucagon and cAMP in cultured hepatocytes. Biochem J. 1997; 326(Pt 1):187–192. 67. Harbrecht BG, Taylor BS, Xu Z, Ramalakshmi S, Ganster RW, Geller DA. cAMP inhibits inducible nitric oxide synthase expression and NF-kappaB-binding activity in cultured rat hepatocytes. J Surg Res. 2001;99:258 –264. 68. Barnes RD, Ward LE, Frank KP, Tyce GM, Hunter LW, Rorie DK. Nitric oxide modulates evoked catecholamine release from canine adrenal medulla. Neuroscience. 2001;104: 1165–1173. 69. Ward LE, Hunter LW, Grabau CE, Tyce GM, Rorie DK. Nitric oxide reduces basal efflux of catecholamines from perfused dog adrenal glands. J Auton Nerv Syst. 1996;61:235–242. 70. Kolo LL, Westfall TC, Macarthur H. Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed. Am J Physiol Heart Circ Physiol. 2004;286:H296 –H303. 71. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol. 1986;78(1 pt 1):76 – 83. 72. Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest. 1980;66: 1072–1080. 73. Preiser J-C, Lejeune P, Roman A, et al. Methylene blue administration in septic shock: a clinical trial. Crit Care Med. 1995;23:259 –264. 74. Donati A, Conti G, Loggi S, et al. Does methylene blue administration to septic shock patients affect vascular permeability and blood volume? Crit Care Med. 2002;30: 2271–2277.

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

75. Viaro F, Dalio MB, Evora PR. Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice? Chest. 2002;122:1061–1066. 76. Evora PRB, Viaro F. The guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutical target. Curr Drug Targets. 2006;7:1195–1204. 77. Evora PR, Roselino CH, Schiaveto PM. Methylene blue in anaphylactic shock [letter]. Ann Emerg Med. 1997;30:240. 78. Oliveira Neto AM, Duarte NM, Vicente WV, Viaro F, Evora PR. Methylene blue: an effective treatment for contrast medium-induced anaphylaxis. Med Sci Monit. 2003;9:CS102CS106. 79. Duarte NM, Oliveira Neto AM, Evora PRB. Utilizac¸a˜o endovenosa do azul de metileno no tratamento do choque anafila´tico [Utilization of intravenous methylene blue in the treatment of anaphylactic shock] [abstract]. Arq Bras Cardiol. 2002;79(suppl III):73. 80. Rodrigues JM, Pazin Filho A, Rodrigues AJ, Vicente WV, Evora PRB. Methylene blue for clinical anaphylaxis treatment: a case report .. Sao Paulo Med J. 2007;125:60 – 62. 81. Mestriner Stocche R, Garcia LV, Paulino dos Reis M, Klamt JG, Evora PRB. Uso do azul de metileno no tratamento de choque anafilatico durante anesthesia: relato de caso. [Methylene blue to treat anaphylaxis during anesthesia: case report]. Rev Bras Anestesiol. 2004;54:809 – 814. 82. Sheth SS, Del Duca D, Ergina P, Clarke AE. Methylene blue as a treatment for refractory anaphylaxis [abstract]. J Allergy Clin Immunol. 2007;119 (1 pt 2):S33. 83. Sheth SS, Del Duca D, Ergina P, Clarke A. Methylene blue as a treatment for refractory anaphylaxis. Paper presented at: American Academy of Allergy, Asthma and Immunology Annual Meeting; February 23–27, 2007; San Diego, CA. Posters2View Marathon Multimedia, Faribault, MN. 84. Burrows GE. Methylene blue: effects and disposition in sheep. J Vet Pharmacol Ther. 1984;7:225–231. 85. Menardi AC, Viaro F, Vicente WV, Rodrigues AJ, Evora PR. Hemodynamic and vascular endothelium function studies in healthy pigs after intravenous bolus infusion of methylene blue. Arq Bras Cardiol. 2006;87:525–532. 86. Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000;56:247–250. 87. Clifton J II, Leikin JB. Methylene blue. Am J Ther. 2003;10: 289 –291. 88. Burnakis TG. Inadvertent substitution of methylene blue for indigo carmine to detect premature rupture of membranes. Hosp Pharm. 1995;30:336 –338. 89. Whitwam JG, Taylor AR, White JM. Potential hazard of

VOLUME 99, OCTOBER, 2007

methylene blue. Anaesthesia. 1979;34:181–182. 90. Breault DT, Fisher D, Wiley JF II, Caulkins K, Caperino L. Methylene blue toxicity after oral exposure in an infant [abstract]. J Toxicol Clin Toxicol. 1997;35:504. 91. Bilgin H, Ozcan B, Bilgin T. Methemoglobinemia induced by methylene blue pertubation during laparoscopy. Acta Anaesthesiol Scand. 1998;42:594 –595. 92. Dudley NE. Methylene blue for rapid identification of the parathyroids. BMJ. 1971;3:680 –168. 93. Gordon DL, Airan MC, Thomas W, et al. Parathyroid identification by methylene blue infusion. Br J Surg. 1975;62: 747–749. 94. Bambach CP, Reeve TS. Parathyroid identification by methylene blue infusion. Aust N Z J Surg. 1978;48:314 –317. 95. Wheeler MH, Wade JHS. Intraoperative identification of parathyroid glands: appraisal of methylene blue staining. Am J Surg. 1982;143:713–716. 96. Derom AF, Wallaert PC, Janzing HM, Derom FE. Intraoperative identification of parathyroid glands with methylene blue infusion. Am J Surg. 1993;165:380 –382. 97. Meekin GK. Intraoperative use of methylene blue to localize parathyroid adenoma. Laryngoscope. 1998;108:772–773. 98. Zulian GB, Tullen E, Maton B. Methylene blue for ifosfamideassociated encephalopathy. N Engl J Med. 1995;332: 1239 –1240. 99. Martindale SJ, Stedeford JC. Neurological sequelae following methylene blue injection for parathyroidectomy. Anaesthesia. 2003;58:1041–1042. 100. Bach KK, Lindsay FW, Berg LS, Howard RS. Prolonged postoperative disorientation after methylene blue infusion during parathyroidectomy. Anesth Analg. 2004;99:1573–1574. 101. Kessler MR, Eide T, Humayun B, Poppers PJ. Spurious pulse oximeter desaturation with methylene blue injection. Anesthesiology. 1986;65:435– 436. Erratum in: Anesthesiology. 1987; 66:701. 102. Kirlangitis JJ, Middaugh RE, Zablocki A, Rodriquez F. False indication of arterial oxygen desaturation and methemoglobinemia following injection of methylene blue in urological surgery. Mil Med. 1990;155:260 –262. Requests for reprints should be addressed to: Michael R. Simon, MD Division of Allergy and Clinical Immunology Department of Internal Medicine William Beaumont Hospital Medical Office Building, Suite 303 3535 West 13 Mile Rd Royal Oak, MI 48073 E-mail: [email protected]

313