THE JOURNAL OF
ALLERGY AND
Y VOLUME
NUMBER 6
63
Editorial
Histamine, HI and H2 antihistamines, and immediate hypersensitivity reactions Marshall Plaut, M.D. Baltimore,
Md.
Histamine is a low molecular weight amine which in man is stored predominantly in tissue mast cells and circulating basophils. It is released from mast cells and basophils in response to several stimuli, including antigen-IgE antibody interaction. This interaction is believed to be the initial step in allergic (i.e.. immediate hypersensitivity) reactions. Histamine has a multitude of effects on target tissues, as first shown in the classical experiments of Dale and Laidlaw,3* 4 which established that histamine could induce contraction of many different types of smooth muscle and also.induce marked depression of blood pressure. Analysis of the mechanism of action of histamine became possible after Bovet and Staub”, ’ described the first antihistamine, an agent which could antagonize several of the biologic effects of histamine and reduce symptoms of guinea pig anaphylaxis. More potent antihistamines were then synthesized, and were shown to inhibit competitively histamineinduced contractions of many types of smooth muscle. The dlemonstration of competitive inhibition suggested that histamine acted on specific receptors in target tissues. In the mid-1960s Ash and Schild’ reanalyzed the action of histamine and noted that “standard” antihistamines like diphenhydramine and pyrilamine inhibited some actions of histamine but Reprint requests to: Marshall Plaut, M.D., The Johns Hopkins University School of Medicine, Division of Clinical Immunology, Baltimore, MD 212119. 0091-6749/79/060371+05$00.50/0
0 1979 The C. V. Mosby
did not block others, such as stimulation of gastric acid secretion. They suggested that these latter activities must be mediated by a second type of histamine receptor. The elegant studies of Black and colleagues”, 9 confirmed the existence of two types of histamine receptors (designated histamine type 1 and histamine type 2 and abbreviated here as Hl and H2) by defining a new H2 antihistamine, burimamide, and then two more potent agents, metiamide and cimetidine. Histamine-mediated contraction of bronchial or ileal smooth muscle is mediated by Hl receptors and is blocked by standard (Hl) antihistamines. In contrast, histamine-induced stimulation of gastric acid secretion is mediated by H2 receptors and blocked by burimamide, metiamide, and cimetidine. (Cimetidine is the only clinically available H2 antihistamine.) There are also drugs (none clinically available) which are selective agonists for HI or H2 receptors. ‘3 *-13 2-Methylhistamine, 2-(2-aminoethyl)-pyridine, and 2-(2-aminoethyl)-thiazole are, respectively, increasingly selective Hl agonists (although they all possess significant H2 activity). CMethythistamine and especially dimaprit and impromidine are highly specific H2 agonists. In several tissues, histamine mediates distinct and even opposing effects. While Hl receptors mediate bronchial smooth muscle contraction, in some species, including sheep and perhaps man,i4 H2 receptors in the trachea mediate smooth muscle relaxation. Histamine-induced vascular effects (e.g., increased vascular permeability) formerly were thought to be Co.
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mediated solely by Hl receptors. However, many histamine-induced vascular effects, including cutaneous flushing,‘js I6 are only partially blocked by Hl antihistamines, not altered by H2 antihistamines alone, and are inhibited completely by Hl plus H2 antagonists. Thus vascular responses, including local cutaneous reactions (wheal and flare) are mediated by H 1 and H2 receptors. r7* l8 The affinity of vascular H2 receptors for histamine is apparently tenfold less than that of H 1 receptors.“* lo Histamine has two types of effects on hypersensitivity reactions: “proinflammatory” and “anti-inflammatory” actions.’ Histamine-induced increases in vascular permeability facilitate migration of immunoglobulinsn’ and leukocytes20 to the site of inflammation. The effects of H 1 receptor activation predominate, but H2 receptors may also participate in this action of histamme. The anti-inflammatory actions of histamine are its inhibition of the effector functions of inflammatory cells, including inhibition of histamine release from basophils2* and lysosomal enzyme release from neutrophils,22 and of cytotoxicity,23 MIF production, and proliferation24 of T lymphocytes. These antiinflammatory effects are mediated by H2 receptors. Antigen-IgE antibody interaction results in release of histamine from mast cells and basophils. Large amounts of histamine can be released from these cells in vitro. Histamine also is released in vivo in man. During systemic reactions following challenge of patients with cold urticaria25 and during systemic anaphylaxis, 26high concentrations are present in venous blood. Since histamine can induce effects in target organs that mimic symptoms of rhinitis, asthma, urticaria, and systemic anaphylaxis, and since it is released in the acute forms of these allergic disease states, it is likely to be an important mediator of immediate hypersensitivity reactions. If histamine is the principal mediator of allergic diseases, then it should be possible to treat these diseases successfully with antihistamines. However, it is generally observed that Hl antihistamines are not effective in anaphylaxis or asthma and have only modest effects on alleviating the symptoms of allergic rhinitis.27 There are at least three possible explanations for the therapeutic failure of H 1 antihistamines: (1) Following antigen-induced mediator release, local tissue levels of histamine are so high that they cannot be blocked by clinically obtainable tissue concentrations of antihistamines. (2) Mediators other than histamine (e.g., SRS-A) are important in the pathogenesis of immediate hypersensitivity reactions. (3) The effects of histamine are due to its actions on both HI
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and H2 receptors, and blockade with Hl antihistamines alone is not sufficient. All three of these explanations may be correct. The first hypothesis is supported by observations that, following antigen-induced mediator release, tissue concentrations of histamine may be as high as lo-” M - 10-3M.2”* The second explanation, that several mediators participate in allergic reactions, is substantiated by several lines of evidence. Mediators such as SRS-A and ECF-A are released in vitro’ and can be detected in vivo (e.g., in venous blood following challenge of patients with cold urticaria).“” Recent in vitro studies suggest that SRS-A, and not histamine, is responsible for the “late” (from less than 10 min to greater than 60 min after challenge) prolonged phase of airway smooth muscle contraction of antigenchallenged guinea pig trachea and human bronchus.2’ The third hypothesis, that both Hl and H2 receptor blockade are required to alleviate allergic symptoms, is addressed in the manuscript by Hutchcroft, Moore, and Orange in this issue of the JOURNAL.~~ Before discussing this work, it is useful to review the potential effects of H2 antihistamines, and previous observations in several models of allergy. There are at least six possible effects of H2 antihistamines on immediate hypersensitivity reactions. These include (1) synergy with Hl antihistamines on inhibition of vascular receptors and (2) blockade of the anti-inflammatory receptors for histamine. Other effects include (3) inhibition of metabolism of histamine3’, 32 (burimamide, metiamide, and cimetidine inhibit N-methyltransferase and histaminase, the two enzymes that metabolize histamine, although their potency for enzyme inhibition differs from their potency of receptor blockade); (4) induction of catecholamine release,‘O (5) induction of histidine decarboxylase,33 and (6) possible alteration of the normal turnover rates of H2 receptors (by prolonged blockade of H2 receptors), which might increase tissue sensitivity to histamine. These last two effects probably are not important in short-term experiments. The first and fourth effects would inhibit immediate hypersensitivity reactions, while the second and third would enhance the reactions. Based on our in vitro studies, we had speculated that blockade of anti-inflammatory effects of histamine would be the predominant effect of these antihistamines.’ Previous investigators have examined the effects of H2 antihistamines on five models of allergy: mediator release from sensitized and challenged basophils, mediator release from sensitized and challenged lung, *Also, Lichtenstein LM: Unpublished observations
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mediator release from sensitized and challenged skin, bronchospasm in sensitized and challenged intact animals, and cutaneous reactivity in sensitized and challenged intact animals. The previous studies have reported variable results in these different models: enhanced reactivity, inhibited reactivity, or no effect. H2 antihistamines alone do not affect histamine release from sensitized, challenged human basophils.“’ In sensitized and challenged lung, the H2 antihistamines are reported to augment histamine release (guinea pig),31 augment histamine release and slightly augment SRS-A release (monkey),aj and have variable but generally no significant effect on histamine and SRS-A release (human).36 In sensitized and challenged skin, released histamine was increased but intracellular histamine was unchanged.3i In those models where increased mediators were found, the antihistamines are probably inhibiting histamine metabolism3’ and/or blocking anti-inflammatory receptors 38 In one model of antigen-induced guinea pig bronchospasm, metiamide potentiated the pulmonary response and cimetidine had no effect,38 while in another model cimetidine at high concentrations potentiated bronchospasm. 34 H2 antihistamines had no effect on dog bronchospasm.3g Histamine-induced vascular permeability changes in dog muscle were partially blocked by HI antihistamines, not affected by H2 antihistamines alone, and inhibited most effectively by combinations of H 1 and H2 antihis’amines.40 In this same model,“O vascular permeability induced by compound 48/80 (which, like antigen in sensitized tissues, degranulates mast cells) was not affected by either Hl or H2 antihistamines alone, but was partially blocked by Hl plus H2 antagonists. In man, cutaneous reactivity to compound 48/80 was slightly inhibited by cimetidine, and combinaticns of H 1 antihistamines and cimetidine were more effective inhibitors than Hl antagonists alone.‘” Cimetidine appeared to inhibit the flare better than the wheal response. We have recently found that cimetidine alone does not affect the wheal and induces moclest suppression of the flare reaction in antigen-challenged atopic patients.a’* These observations, modest inhibitory effects of H2 antihistamines on cutaneous immediate reactivity, suggest that the major effect of these changes is to block vascular receptors. Inhibitory effects on anti-inflammatory receptors are not detectable. (These effects of the H2 antihistamines are also partially explained by their *Also, Wolfe JD. Plaut M, Norman PS, Lichtenstein LM: Unpublished observations.
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induction of catecholamine release,‘? although the potency of cimetidine in inducing catecholamine release is uncertain.) The effects of cimetidine on delayed cutaneous reactivity are also variable. In one study, cimetidine was reported to enhance delayed skin tests,“* but in another study4’ using a different patient population, it had no apparent effect. The most striking feature of these studies is the inconsistency of the effects of H2 antihistamines in different systems. One of the reports described above notes differences between metiamide and cimetidine.“” These differences are not readily explained, since these two agents are equipotent as antagonists of H2 receptors, including H2 receptors on human basophils and mouse cytotoxic lymphocytes.l:%* Some of the variability can be explained by differential sensitivity of different species and tissues to histamine. Clearly, there is no simple way to synthesize the results of all these investigations, although the effects of H2 antihistamines on immediate cutaneous reactivity (inhibition) appear to be more consistent than their effects on bronchospasm. In this issue of the JOURNAL, Hutchcroft et al.30 have examined the effects in monkey skin of an HI antihistamine (chlorpheniramine), cimetidine, or combinations of both drugs. They have measured the area of the wheal induced by histamine and by passive cutaneous anaphylaxis (PCA) and reversed PCA (RPCA) reactions. Because they have studied reactivity over a wide range of concentrations of histamine, of sensitizing serum (for PCA), and of anti-IgE (for RPCA), they can demonstrate convincingly that the effects of antihistamines are consistent over the doseresponse curves. They have found that cimetidine alone at intermediate doses has no effect on immediate skin tests to histamine or PCA reactions to antigen, while at high concentrations it inhibits. Chlorpheniramine inhibits cutaneous reactivity to both histamine and antigen (as in other studies,‘x, Aobut in contrast to the results of Perper et a1.14)Their most interesting observation is that chlorpheniramine and cimetidine together are possibly synergistic in their inhibition not only of histamine skin tests, but also of antigen-induced PCA reactions. However, cimetidine alone does not inhibit RPCA reactions and does not potentiate chlorpheniramine inhibition of RPCA reactions. These results agree with the two analogous studies cited earlier.‘“, 4o However, the differences between the effects of cimetidine on PCA vs RPCA reactions *Also. Lichtenstein LM: Unpublished observations
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are not readily explained. Also, the apparent synergy of chlorpheniramine and cimetidine on histamine and PCA wheals is not proved statistically. Thus, the results of Hutchcroft et a1.30 must be interpreted cautiously. If the results can be generalized and synthesized with those of other studies,“, lR*40,41then two important conclusions are apparent: (1) histamine is the predominant, if not the only, mediator of the increased vascular permeability of antigen-induced PCA reactions, since a combination of Hl plus H2 antihistamines completely inhibits the wheal, and (2) the predominant action of H2 antihistamines in the skin of monkey (and perhaps man) is blockade of vascular H2 receptors, an action which is synergistic with that of H 1 antihistamines on vascular Hl receptors. We have already pointed out that H2 antihistamines may have different, and even opposite, effects in other experimental systems (e.g., in the lung). Bronchospasm is not mediated by vascular H2 receptors, and thus other actions of cimetidine, such as inhibition of histamine metabolism, may be more important in the lung. It also would be useful to repeat the present study in order to determine whether the actions of Hl and H2 antihistamines are truly synergistic. However, the results, and those of other studies, suggest that Hl and H2 receptor blockade might be helpful for treating some cutaneous manifestations of allergic diseases. Since urticarial reactions are induced by cutaneous release of mediators and resultant vascular permeability changes, these reactions may be the most logical ones to study. One brief report45 has suggested that combinations of Hl and H2 antihistamines may be beneficial in some patients with chronic utticaria. Another study of chronic urticaria46 has repotted that patients treated with Hl and H2 antihistamines had lower symptom scores than those treated with Hl antihistamines alone, but the differences in scores were not significant. Several other investigators are also studying combinations of antihistamines. We would anticipate that controlled, double-blind studies with optimal doses of H 1 and H2 antihistamines will soon define the effectiveness of this therapy in allergic disorders. REFERENCES I. Plaut M, Lichtenstein LM: Histamine, 5-hydroxytryptamine, SRS-A: Discussion of type I hypersensitivity (anaphylaxis), in Vane JR, Ferreira SH, editors: Handbook of experimental pharmacology, vol. SO/I: Inflammation. Berlin, 1978, Springer-Verlag, p. 345. 2. Douglas WW: Histamine and antihistamines: 5-Hydroxytryp tamine and antagonists, in Goodman LS, Gilman A, editors: The pharmacologic basis of therapeutics, ed. 5. New York, 1975, MacMillan Publishing Co., Inc., p. 590.
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3. Dale HH, Laidlaw PP: The physiological action of /3-imidazolylethylamine. J Physiol (Land) 41:318, 19 10. 4. Dale HH, Laidlaw PP: Histamine shock. J Physiol (Lond) 52:355, 1919. 5. Bovet D, Staub A-M: Action protectrice des ethers phenoliques au tours de l’intoxication histaminique. Compt rend Sot de Biol 125~547, 1937. 6. Staub A-M, Bovet D: Action de la thymoxyethyldiethylamine (929 F) et des ethers phinoliques sur le droc anaphylactique du cobaye. Compt rend Sot de Biol 125818, 1937. 7. Ash ASF, Schild HO: Receptors mediating some actions of histamine. Br J Pharmacol 27~427, 1966. 8. Black JW, Duncan WAM, Durant GJ, Ganellin CR, Parsons ME: Definition and antagonism of histamine HZreceptors. Nature 236~385, 1972. 9. Black JW: Histamine receptors, in Proc 6th Int Cong Pharmacology, Klinge E, editor: Helsinki, 1975, Finnish Pharmacological Society, vol. I, p. 3. 10. Owen DAA: Histamine receptors in the cardiovascular system. Gen Pharmacol 8: 141, 1977. 11. Durant GJ, Ganellin CR, Parsons ME: Chemical differentiation of histamine HI- and H2receptor antagonists. J Med Chem l&905, 1975. 12. Parsons ME, Owen DAA, Ganellin CR, Durant CJ: Dimaprit-(S-(3-(N,N-dimethylamino)-propyl)isothiourea)-a highly specific H2 receptor agonist. Part 1. Pharmacology. Agents Actions 7:31, 1977. 13. Durant GJ, Duncan WAM, Ganellin CR, Parsons ME, Blakemore RC, Rasmussen AC: Impromidine (SK and F 92676) is a very potent and specific agonist for histamine H2 receptors. Nature 276~403, 1978. 14. Dunlop LS, Smith AP: The effect of histamine antagonists on antigen-induced contractions of sensitized human bronchus in vitro. Br J Pharmacol 5k475P, 1977. (Abst.) 15. Wyllie JH: Hesselbo T, Black JW: Effects in man of histamine H2receptor blockade by burimamide. Lancet 2: 1117, 1972. 16. Roberts LJ, II, Marney SR, Oates JA: Blockade of the flush associated with metastatic gastric carcinoid by combined histamine HI and H2 receptor antagonists. Evidence for an important role of H2 receptors in human vasculature. N Engl J Med 300~236, 1979. 17. Robertson I, Greaves MW: Responses of human skin blood vessels to synthetic histamine analogues. Br J Clin Pharmacol 5:319, 1978. 18. Marks R, Greaves MW: Vascular reactions to histamine and compound 48/80 in human skin: Suppression by a histamine HZreceptor blocking agent. Br J Clin Pharmacol4:367, 1977. 19. Kniker WT, Cochrane CG: Pathogenic factors in vascular lesions of experimental serum sickness. J Exp Med 122~83, 1965. 20. Schwartz A, Askenase PW, Gershon RK: The effect of locally injected vasoactive amines on the elicitation of delayed-type hypersensitivity. J Immunol 118: 159, 1977. 21. Lichtenstein LM, Gillespie E: The effects of the Hl and H2 antihistamines on “allergic” histamine release and its inhibition by histamine. J Pharmacol Exp Ther 192441, 1975. 22. Sosman J, Busse W: Histamine inhibition of neutrophil lyso somal enzyme release: An H2 histamine receptor response. Science 194~737, 1976. 23. Plaut M, Lichtenstein LM, Henney CS: Properties of a sub population of T cells bearing histamine receptors. J Clin Invest 55~856, 1975. 24. Rocklin RE: Modulation of cellular immune responses in viva and in vitro by histamine receptor-bearing lymphocytes. J Clin Invest 57: 105 1, 1976.
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25. Kaplan AP. Gray L, Shaff RE, Horakowa 2. Beaven MA: 1tt t?t,o studies of mediator release in cold urticaria and cholinergic urticaria.
J ALLERGY CLIN IMMUNOL 55394,
1975.
26. Kaplan Al’, Hunt KJ, Sobotka AK. Smith P, Horakova Z. Ciralnick H, Lichtenstein LM: Human anaphylaxis: A study of mediator systems. Clin Res 25:361A, 1977. (Abst.) 27. Valentine MD, Norman PS, Lichtenstein LM: Evaluation of an antihistamine in ragweed hay fever, in McMahon FG, editor: Principles and techniques of human research therapeutics. Mt. Kisco. N. Y., 1974, Futura Publishing Co., p. 227. 28. Adams GK 111. Lichtenstein LM: In vitro studies of antigeninduced bronchospasm: Effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen. J Immunol 122555. 1979. 29. Sorer NA. Wasserman Sl. Austen KF: Cold urticaria: Release of histamine and ECF-A during cold challenge. N Engl J Med 294:687, 1976. 30. Hutchcroft BJ. Moore EC, Orange RP: The effects of H, and H, receptor antagonism on the response of monkey skin to intradermal histamine, reverse-type anaphylaxis, and passive cutaneous anaphylaxis. J ALLERGY CLIN IMMUNOL 63376, 1979. 31. Maslinski C: Histamine and its metabolism in mammals. Part I. Chemistry and formation of histamine. Part II. Catabolism of histatrine and histamme liberation. Agents Actions 5:X9 and 183. 1975. 32. Thomas LL, Bochner BS, Lichtenstein LM: Inhibition of human polymorphonuclear leukocyte-derived histaminase activity by H2 antagonists. Biochem Pharmacol 222562, 1978. 33. M.mdsley DV, Kobayashi Y, Williamson E, Bovaird L: H2receptor blockade and stimulation of histidine decarboxylase. Nature [New Biol] 245: 148, 1973. 34. Dulabh R, Vickers MR: The effects of H2-receptor antagonists on anaphylaxis in the guinea pig. Agents Actions 8:559, 1978. 35. Chakrin LW, Krell RD, Mengel J, Young D, Zaher C, Wardell JR Jr: Ef ‘ect of a histamine H2-receptor antagonist on immunologically induced mediator release in vitro. Agents Actions 4:297. 1974.
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36. Kaliner M: Human lung tissue and anaphylaxis: The effects of histamine on the immunologic release of mediators. Am Rev Respir Dis 118: 1015, 1978. 37. Yamamoto S, Francis D, Greaves MW:ln vilro andphylaxis in guinea pig skin: Amplification by burimamide. J Invest Dermatol 67:696, 1976. 38. Drazen JM, Venugopalan CS, Soter NA: H2 receptor mediated inhibition of immediate type hypersensitivity reactions in I+VO. Am Rev Respir Dis 117:479, 1978. 39. Krell RD. Chakrin LW: The effects of a histamine H2 receptor antagonist on in vitro and in viva canine models of allergic asthma. Pharmacologist 18~204. 1976. 40. Powell JR, Brody MJ: Participation of H 1 and H2 histamine receptors in physiological vasodilator responses. Am J Physiol
231: 1002, 1976. 41. Wolfe JD, Plaut M, Norman PS, Lichtenstein LM: The effect of an H2 receptor antagonist on immediate and delayed skin test reactivity in man. J ALLERGY Cr IN IMMUNOL 63:208, 1979. (Abst.) 42. Avella J. Binder HJ, Madsen JE, Askenase PW: Effect of histamine HZ-receptor antagonists on delayed hypersensitivity. Lancet 1:624, 1978. 43. Plaut M, Berman IJ: Histamine receptors on human and mouse lymphocytes. J ALLERGY CLIN IMMUNOL 61:132, 197X. (Abst.) 44. Perper RJ, Sanda M, Lichtenstein LM: The relationship of in ~,irro and in viva allergic histamine release: Inhibition in primates by CAMP active agents. Int Arch Allergy Appl Immunol 43:837. 1972. 45. Phanuphak P, Schocket A, Kohler PF: Treatment of chronic idiopathic urticaria with combined HI and H2 blockers. Clin Allergy 8:429, 1978. 46. Commens CA, Graves MW: Cimetidine in chronic idiopathic urticaria: A randomized double-blind study. Br J Dermatol 99:675. 1978.
ALLERGY AND
Y VOLUME
NUMBER 6
63
Editorial
Histamine, HI and H2 antihistamines, and immediate hypersensitivity reactions Marshall Plaut, M.D. Baltimore,
Md.
Histamine is a low molecular weight amine which in man is stored predominantly in tissue mast cells and circulating basophils. It is released from mast cells and basophils in response to several stimuli, including antigen-IgE antibody interaction. This interaction is believed to be the initial step in allergic (i.e.. immediate hypersensitivity) reactions. Histamine has a multitude of effects on target tissues, as first shown in the classical experiments of Dale and Laidlaw,3* 4 which established that histamine could induce contraction of many different types of smooth muscle and also.induce marked depression of blood pressure. Analysis of the mechanism of action of histamine became possible after Bovet and Staub”, ’ described the first antihistamine, an agent which could antagonize several of the biologic effects of histamine and reduce symptoms of guinea pig anaphylaxis. More potent antihistamines were then synthesized, and were shown to inhibit competitively histamineinduced contractions of many types of smooth muscle. The dlemonstration of competitive inhibition suggested that histamine acted on specific receptors in target tissues. In the mid-1960s Ash and Schild’ reanalyzed the action of histamine and noted that “standard” antihistamines like diphenhydramine and pyrilamine inhibited some actions of histamine but Reprint requests to: Marshall Plaut, M.D., The Johns Hopkins University School of Medicine, Division of Clinical Immunology, Baltimore, MD 212119. 0091-6749/79/060371+05$00.50/0
0 1979 The C. V. Mosby
did not block others, such as stimulation of gastric acid secretion. They suggested that these latter activities must be mediated by a second type of histamine receptor. The elegant studies of Black and colleagues”, 9 confirmed the existence of two types of histamine receptors (designated histamine type 1 and histamine type 2 and abbreviated here as Hl and H2) by defining a new H2 antihistamine, burimamide, and then two more potent agents, metiamide and cimetidine. Histamine-mediated contraction of bronchial or ileal smooth muscle is mediated by Hl receptors and is blocked by standard (Hl) antihistamines. In contrast, histamine-induced stimulation of gastric acid secretion is mediated by H2 receptors and blocked by burimamide, metiamide, and cimetidine. (Cimetidine is the only clinically available H2 antihistamine.) There are also drugs (none clinically available) which are selective agonists for HI or H2 receptors. ‘3 *-13 2-Methylhistamine, 2-(2-aminoethyl)-pyridine, and 2-(2-aminoethyl)-thiazole are, respectively, increasingly selective Hl agonists (although they all possess significant H2 activity). CMethythistamine and especially dimaprit and impromidine are highly specific H2 agonists. In several tissues, histamine mediates distinct and even opposing effects. While Hl receptors mediate bronchial smooth muscle contraction, in some species, including sheep and perhaps man,i4 H2 receptors in the trachea mediate smooth muscle relaxation. Histamine-induced vascular effects (e.g., increased vascular permeability) formerly were thought to be Co.
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mediated solely by Hl receptors. However, many histamine-induced vascular effects, including cutaneous flushing,‘js I6 are only partially blocked by Hl antihistamines, not altered by H2 antihistamines alone, and are inhibited completely by Hl plus H2 antagonists. Thus vascular responses, including local cutaneous reactions (wheal and flare) are mediated by H 1 and H2 receptors. r7* l8 The affinity of vascular H2 receptors for histamine is apparently tenfold less than that of H 1 receptors.“* lo Histamine has two types of effects on hypersensitivity reactions: “proinflammatory” and “anti-inflammatory” actions.’ Histamine-induced increases in vascular permeability facilitate migration of immunoglobulinsn’ and leukocytes20 to the site of inflammation. The effects of H 1 receptor activation predominate, but H2 receptors may also participate in this action of histamme. The anti-inflammatory actions of histamine are its inhibition of the effector functions of inflammatory cells, including inhibition of histamine release from basophils2* and lysosomal enzyme release from neutrophils,22 and of cytotoxicity,23 MIF production, and proliferation24 of T lymphocytes. These antiinflammatory effects are mediated by H2 receptors. Antigen-IgE antibody interaction results in release of histamine from mast cells and basophils. Large amounts of histamine can be released from these cells in vitro. Histamine also is released in vivo in man. During systemic reactions following challenge of patients with cold urticaria25 and during systemic anaphylaxis, 26high concentrations are present in venous blood. Since histamine can induce effects in target organs that mimic symptoms of rhinitis, asthma, urticaria, and systemic anaphylaxis, and since it is released in the acute forms of these allergic disease states, it is likely to be an important mediator of immediate hypersensitivity reactions. If histamine is the principal mediator of allergic diseases, then it should be possible to treat these diseases successfully with antihistamines. However, it is generally observed that Hl antihistamines are not effective in anaphylaxis or asthma and have only modest effects on alleviating the symptoms of allergic rhinitis.27 There are at least three possible explanations for the therapeutic failure of H 1 antihistamines: (1) Following antigen-induced mediator release, local tissue levels of histamine are so high that they cannot be blocked by clinically obtainable tissue concentrations of antihistamines. (2) Mediators other than histamine (e.g., SRS-A) are important in the pathogenesis of immediate hypersensitivity reactions. (3) The effects of histamine are due to its actions on both HI
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and H2 receptors, and blockade with Hl antihistamines alone is not sufficient. All three of these explanations may be correct. The first hypothesis is supported by observations that, following antigen-induced mediator release, tissue concentrations of histamine may be as high as lo-” M - 10-3M.2”* The second explanation, that several mediators participate in allergic reactions, is substantiated by several lines of evidence. Mediators such as SRS-A and ECF-A are released in vitro’ and can be detected in vivo (e.g., in venous blood following challenge of patients with cold urticaria).“” Recent in vitro studies suggest that SRS-A, and not histamine, is responsible for the “late” (from less than 10 min to greater than 60 min after challenge) prolonged phase of airway smooth muscle contraction of antigenchallenged guinea pig trachea and human bronchus.2’ The third hypothesis, that both Hl and H2 receptor blockade are required to alleviate allergic symptoms, is addressed in the manuscript by Hutchcroft, Moore, and Orange in this issue of the JOURNAL.~~ Before discussing this work, it is useful to review the potential effects of H2 antihistamines, and previous observations in several models of allergy. There are at least six possible effects of H2 antihistamines on immediate hypersensitivity reactions. These include (1) synergy with Hl antihistamines on inhibition of vascular receptors and (2) blockade of the anti-inflammatory receptors for histamine. Other effects include (3) inhibition of metabolism of histamine3’, 32 (burimamide, metiamide, and cimetidine inhibit N-methyltransferase and histaminase, the two enzymes that metabolize histamine, although their potency for enzyme inhibition differs from their potency of receptor blockade); (4) induction of catecholamine release,‘O (5) induction of histidine decarboxylase,33 and (6) possible alteration of the normal turnover rates of H2 receptors (by prolonged blockade of H2 receptors), which might increase tissue sensitivity to histamine. These last two effects probably are not important in short-term experiments. The first and fourth effects would inhibit immediate hypersensitivity reactions, while the second and third would enhance the reactions. Based on our in vitro studies, we had speculated that blockade of anti-inflammatory effects of histamine would be the predominant effect of these antihistamines.’ Previous investigators have examined the effects of H2 antihistamines on five models of allergy: mediator release from sensitized and challenged basophils, mediator release from sensitized and challenged lung, *Also, Lichtenstein LM: Unpublished observations
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mediator release from sensitized and challenged skin, bronchospasm in sensitized and challenged intact animals, and cutaneous reactivity in sensitized and challenged intact animals. The previous studies have reported variable results in these different models: enhanced reactivity, inhibited reactivity, or no effect. H2 antihistamines alone do not affect histamine release from sensitized, challenged human basophils.“’ In sensitized and challenged lung, the H2 antihistamines are reported to augment histamine release (guinea pig),31 augment histamine release and slightly augment SRS-A release (monkey),aj and have variable but generally no significant effect on histamine and SRS-A release (human).36 In sensitized and challenged skin, released histamine was increased but intracellular histamine was unchanged.3i In those models where increased mediators were found, the antihistamines are probably inhibiting histamine metabolism3’ and/or blocking anti-inflammatory receptors 38 In one model of antigen-induced guinea pig bronchospasm, metiamide potentiated the pulmonary response and cimetidine had no effect,38 while in another model cimetidine at high concentrations potentiated bronchospasm. 34 H2 antihistamines had no effect on dog bronchospasm.3g Histamine-induced vascular permeability changes in dog muscle were partially blocked by HI antihistamines, not affected by H2 antihistamines alone, and inhibited most effectively by combinations of H 1 and H2 antihis’amines.40 In this same model,“O vascular permeability induced by compound 48/80 (which, like antigen in sensitized tissues, degranulates mast cells) was not affected by either Hl or H2 antihistamines alone, but was partially blocked by Hl plus H2 antagonists. In man, cutaneous reactivity to compound 48/80 was slightly inhibited by cimetidine, and combinaticns of H 1 antihistamines and cimetidine were more effective inhibitors than Hl antagonists alone.‘” Cimetidine appeared to inhibit the flare better than the wheal response. We have recently found that cimetidine alone does not affect the wheal and induces moclest suppression of the flare reaction in antigen-challenged atopic patients.a’* These observations, modest inhibitory effects of H2 antihistamines on cutaneous immediate reactivity, suggest that the major effect of these changes is to block vascular receptors. Inhibitory effects on anti-inflammatory receptors are not detectable. (These effects of the H2 antihistamines are also partially explained by their *Also, Wolfe JD. Plaut M, Norman PS, Lichtenstein LM: Unpublished observations.
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induction of catecholamine release,‘? although the potency of cimetidine in inducing catecholamine release is uncertain.) The effects of cimetidine on delayed cutaneous reactivity are also variable. In one study, cimetidine was reported to enhance delayed skin tests,“* but in another study4’ using a different patient population, it had no apparent effect. The most striking feature of these studies is the inconsistency of the effects of H2 antihistamines in different systems. One of the reports described above notes differences between metiamide and cimetidine.“” These differences are not readily explained, since these two agents are equipotent as antagonists of H2 receptors, including H2 receptors on human basophils and mouse cytotoxic lymphocytes.l:%* Some of the variability can be explained by differential sensitivity of different species and tissues to histamine. Clearly, there is no simple way to synthesize the results of all these investigations, although the effects of H2 antihistamines on immediate cutaneous reactivity (inhibition) appear to be more consistent than their effects on bronchospasm. In this issue of the JOURNAL, Hutchcroft et al.30 have examined the effects in monkey skin of an HI antihistamine (chlorpheniramine), cimetidine, or combinations of both drugs. They have measured the area of the wheal induced by histamine and by passive cutaneous anaphylaxis (PCA) and reversed PCA (RPCA) reactions. Because they have studied reactivity over a wide range of concentrations of histamine, of sensitizing serum (for PCA), and of anti-IgE (for RPCA), they can demonstrate convincingly that the effects of antihistamines are consistent over the doseresponse curves. They have found that cimetidine alone at intermediate doses has no effect on immediate skin tests to histamine or PCA reactions to antigen, while at high concentrations it inhibits. Chlorpheniramine inhibits cutaneous reactivity to both histamine and antigen (as in other studies,‘x, Aobut in contrast to the results of Perper et a1.14)Their most interesting observation is that chlorpheniramine and cimetidine together are possibly synergistic in their inhibition not only of histamine skin tests, but also of antigen-induced PCA reactions. However, cimetidine alone does not inhibit RPCA reactions and does not potentiate chlorpheniramine inhibition of RPCA reactions. These results agree with the two analogous studies cited earlier.‘“, 4o However, the differences between the effects of cimetidine on PCA vs RPCA reactions *Also. Lichtenstein LM: Unpublished observations
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are not readily explained. Also, the apparent synergy of chlorpheniramine and cimetidine on histamine and PCA wheals is not proved statistically. Thus, the results of Hutchcroft et a1.30 must be interpreted cautiously. If the results can be generalized and synthesized with those of other studies,“, lR*40,41then two important conclusions are apparent: (1) histamine is the predominant, if not the only, mediator of the increased vascular permeability of antigen-induced PCA reactions, since a combination of Hl plus H2 antihistamines completely inhibits the wheal, and (2) the predominant action of H2 antihistamines in the skin of monkey (and perhaps man) is blockade of vascular H2 receptors, an action which is synergistic with that of H 1 antihistamines on vascular Hl receptors. We have already pointed out that H2 antihistamines may have different, and even opposite, effects in other experimental systems (e.g., in the lung). Bronchospasm is not mediated by vascular H2 receptors, and thus other actions of cimetidine, such as inhibition of histamine metabolism, may be more important in the lung. It also would be useful to repeat the present study in order to determine whether the actions of Hl and H2 antihistamines are truly synergistic. However, the results, and those of other studies, suggest that Hl and H2 receptor blockade might be helpful for treating some cutaneous manifestations of allergic diseases. Since urticarial reactions are induced by cutaneous release of mediators and resultant vascular permeability changes, these reactions may be the most logical ones to study. One brief report45 has suggested that combinations of Hl and H2 antihistamines may be beneficial in some patients with chronic utticaria. Another study of chronic urticaria46 has repotted that patients treated with Hl and H2 antihistamines had lower symptom scores than those treated with Hl antihistamines alone, but the differences in scores were not significant. Several other investigators are also studying combinations of antihistamines. We would anticipate that controlled, double-blind studies with optimal doses of H 1 and H2 antihistamines will soon define the effectiveness of this therapy in allergic disorders. REFERENCES I. Plaut M, Lichtenstein LM: Histamine, 5-hydroxytryptamine, SRS-A: Discussion of type I hypersensitivity (anaphylaxis), in Vane JR, Ferreira SH, editors: Handbook of experimental pharmacology, vol. SO/I: Inflammation. Berlin, 1978, Springer-Verlag, p. 345. 2. Douglas WW: Histamine and antihistamines: 5-Hydroxytryp tamine and antagonists, in Goodman LS, Gilman A, editors: The pharmacologic basis of therapeutics, ed. 5. New York, 1975, MacMillan Publishing Co., Inc., p. 590.
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3. Dale HH, Laidlaw PP: The physiological action of /3-imidazolylethylamine. J Physiol (Land) 41:318, 19 10. 4. Dale HH, Laidlaw PP: Histamine shock. J Physiol (Lond) 52:355, 1919. 5. Bovet D, Staub A-M: Action protectrice des ethers phenoliques au tours de l’intoxication histaminique. Compt rend Sot de Biol 125~547, 1937. 6. Staub A-M, Bovet D: Action de la thymoxyethyldiethylamine (929 F) et des ethers phinoliques sur le droc anaphylactique du cobaye. Compt rend Sot de Biol 125818, 1937. 7. Ash ASF, Schild HO: Receptors mediating some actions of histamine. Br J Pharmacol 27~427, 1966. 8. Black JW, Duncan WAM, Durant GJ, Ganellin CR, Parsons ME: Definition and antagonism of histamine HZreceptors. Nature 236~385, 1972. 9. Black JW: Histamine receptors, in Proc 6th Int Cong Pharmacology, Klinge E, editor: Helsinki, 1975, Finnish Pharmacological Society, vol. I, p. 3. 10. Owen DAA: Histamine receptors in the cardiovascular system. Gen Pharmacol 8: 141, 1977. 11. Durant GJ, Ganellin CR, Parsons ME: Chemical differentiation of histamine HI- and H2receptor antagonists. J Med Chem l&905, 1975. 12. Parsons ME, Owen DAA, Ganellin CR, Durant CJ: Dimaprit-(S-(3-(N,N-dimethylamino)-propyl)isothiourea)-a highly specific H2 receptor agonist. Part 1. Pharmacology. Agents Actions 7:31, 1977. 13. Durant GJ, Duncan WAM, Ganellin CR, Parsons ME, Blakemore RC, Rasmussen AC: Impromidine (SK and F 92676) is a very potent and specific agonist for histamine H2 receptors. Nature 276~403, 1978. 14. Dunlop LS, Smith AP: The effect of histamine antagonists on antigen-induced contractions of sensitized human bronchus in vitro. Br J Pharmacol 5k475P, 1977. (Abst.) 15. Wyllie JH: Hesselbo T, Black JW: Effects in man of histamine H2receptor blockade by burimamide. Lancet 2: 1117, 1972. 16. Roberts LJ, II, Marney SR, Oates JA: Blockade of the flush associated with metastatic gastric carcinoid by combined histamine HI and H2 receptor antagonists. Evidence for an important role of H2 receptors in human vasculature. N Engl J Med 300~236, 1979. 17. Robertson I, Greaves MW: Responses of human skin blood vessels to synthetic histamine analogues. Br J Clin Pharmacol 5:319, 1978. 18. Marks R, Greaves MW: Vascular reactions to histamine and compound 48/80 in human skin: Suppression by a histamine HZreceptor blocking agent. Br J Clin Pharmacol4:367, 1977. 19. Kniker WT, Cochrane CG: Pathogenic factors in vascular lesions of experimental serum sickness. J Exp Med 122~83, 1965. 20. Schwartz A, Askenase PW, Gershon RK: The effect of locally injected vasoactive amines on the elicitation of delayed-type hypersensitivity. J Immunol 118: 159, 1977. 21. Lichtenstein LM, Gillespie E: The effects of the Hl and H2 antihistamines on “allergic” histamine release and its inhibition by histamine. J Pharmacol Exp Ther 192441, 1975. 22. Sosman J, Busse W: Histamine inhibition of neutrophil lyso somal enzyme release: An H2 histamine receptor response. Science 194~737, 1976. 23. Plaut M, Lichtenstein LM, Henney CS: Properties of a sub population of T cells bearing histamine receptors. J Clin Invest 55~856, 1975. 24. Rocklin RE: Modulation of cellular immune responses in viva and in vitro by histamine receptor-bearing lymphocytes. J Clin Invest 57: 105 1, 1976.
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36. Kaliner M: Human lung tissue and anaphylaxis: The effects of histamine on the immunologic release of mediators. Am Rev Respir Dis 118: 1015, 1978. 37. Yamamoto S, Francis D, Greaves MW:ln vilro andphylaxis in guinea pig skin: Amplification by burimamide. J Invest Dermatol 67:696, 1976. 38. Drazen JM, Venugopalan CS, Soter NA: H2 receptor mediated inhibition of immediate type hypersensitivity reactions in I+VO. Am Rev Respir Dis 117:479, 1978. 39. Krell RD. Chakrin LW: The effects of a histamine H2 receptor antagonist on in vitro and in viva canine models of allergic asthma. Pharmacologist 18~204. 1976. 40. Powell JR, Brody MJ: Participation of H 1 and H2 histamine receptors in physiological vasodilator responses. Am J Physiol
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