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Histamine H1 receptors are involved in mouse nasal allergic responses: a demonstration with H1 receptor-deficient mice
International Immunopharmacology 2 (2002) 745 – 750 www.elsevier.com/locate/intimp
Histamine H1 receptors are involved in mouse nasal allergic responses: a demonstration with H1 receptor-deficient mice Ryoji Kayasuga a, Yukio Sugimoto a, Takeshi Watanabe b, Chiaki Kamei a,* a Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
b
Received 12 December 2001; received in revised form 29 January 2002; accepted 4 February 2002
Abstract The role of histamine H1 receptors in nasal allergic symptoms (sneezing and nasal rubbing) were studied using histamine H1 receptor-deficient mice. Intranasal instillation of histamine solution resulted in significant increases in sneezing and nasal rubbing in wild-type mice, whereas no increases were observed in histamine H1 receptor-deficient mice. The histamine H1 receptor agonist 2-pyridylethylamine induced sneezing and nasal rubbing in a dose-dependent manner in wild-type mice, but no such increase was found in histamine H1 receptor-deficient mice. On the other hand, the histamine H2 receptor agonist dimaprit did not increase sneezing and nasal rubbing in wild-type mice. Histamine H1 receptor antagonists such as chlorpheniramine and epinastine significantly inhibited nasal allergic symptoms caused by histamine, but the histamine H2 receptor antagonists cimetidine and famotidine showed no effect. No additional effects were observed by combined use of chlorpheniramine and cimetidine or famotidine compared with cimetidine or famotidine alone. These results suggested that histamine H1 receptors play an important role in nasal allergy symptoms induced by histamine. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Nasal allergic symptoms; Sneezing; Nasal rubbing; Histamine H1 receptor; Histamine
1. Introduction Allergic rhinitis is a chronic inflammatory disease characterized by sneezing, itching, congestion and rhinorrhea in humans [1]. Recently, we reported a chronic allergic rhinitis model in rats showing nasal symptoms such as sneezing and nasal rubbing [2]. The chemical mediators involved in allergic rhinitis are
*
Corresponding author. Tel./fax: +81-86-251-7939. E-mail address: [email protected] (C. Kamei).
thought to be histamine, leukotrienes, prostaglandins, thromboxanes, kinins, etc. [1,3 – 5]. Among these mediators, histamine is a substance that causes an increase in vascular permeability and stimulation of sensory nerves [6,7]. It is well known that actions on sensory nerves precipitate itching and sneezing. On the other hand, histamine H1 receptor antagonists are known to be beneficial in relieving nasal itching, sneezing and rhinorrhea in patients with allergic rhinitis [8,9], and they also significantly inhibited histamine-induced tickling, sneezing and discharge in volunteers [10]. Cimetidine added to conventional histamine H1 receptor antagonists may be of some additive benefit in the treatment of seasonal allergic
1567-5769/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 7 - 5 7 6 9 ( 0 2 ) 0 0 0 1 0 - 3
746
R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
rhinitis [11]. However, one study suggested that application of cimetidine significantly worsened secretion and sneezing as compared to a placebo control in humans [12]. Therefore, the present study was performed to clarify the role of histamine H1 receptors in nasal symptoms using histamine H1 receptor-deficient mice.
sneezing and nasal rubbing movements were counted for 10 min by the method of Sugimoto et al. [2].
2. Materials and methods 2.1. Animals Male histamine H1 receptor-deficient and wild-type mice weighing 15 –22 g were used. Histamine H1 receptor-deficient mice were generated by homologous recombination as described [13] and bred in our laboratory. Male wild-type mice (C57BL/6) were obtained from Japan SLC, Shizuoka. Both strains were housed in a temperature-controlled room at 24 F 2 jC with 55 F 15% humidity and were given food and water ad libitum. 2.2. Reagents Histamine dihydrochloride (Nacalai Tesque, Kyoto, Japan), 2-pyridylethylamine dihydrochloride (kindly provided by Smith Kline and French Laboratories, Welwyn Garden City, Herts, UK) and dimaprit dihydrochloride (kindly provided by Smith Kline and French Laboratories) were used. These drugs were dissolved in saline and administered intranasally. D-Chlorpheniramine maleate (Sigma, St. Louis, MO, USA), epinastine hydrochloride (Bo¨ehringer Ingelheim, Ingelheim, Germany), cimetidine (kindly provided by Smith Kline and French Laboratories) and famotidine (kindly provided by Smith Kline and French Laboratories) were suspended in 5% gum arabic and were administered orally. 2.3. Evaluation of nasal symptoms Before the experiment, the animals were placed into an observation cage (32 22 10 cm) for about 10 min for acclimatization. After nasal instillation of 1 Al of histamine solution into the bilateral nasal cavities, the animals were placed into the observation cage (one animal/cage), and the numbers of
Fig. 1. Sneezing and nasal rubbing induced by histamine in wildtype mice and histamine H1 receptor-deficient mice. Histamine was applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Results show (A) sneezing and (B) nasal rubbing induced by histamine. Wild-type mice (open columns); H1 receptor-deficient mice (hatched columns). Each column and vertical bar shows the mean F S.E.M. of 10 experiments. *, **: Significantly different from saline-treated group at P < 0.05 and P < 0.01, respectively.
R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
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2.4. Effects of drugs on nasal symptoms
2.5. Statistical analysis
In this study, test drugs were administered orally 1 h before nasal instillation of histamine (0.5 Ag/site), and the numbers of sneezing and nasal rubbing movements induced by histamine were counted for 10 min.
Data are presented as means F S.E.M. Statistical analysis was performed by one-way analysis of variance with Dunnett’s test. Probability values less than 0.05 were considered significant.
Fig. 2. Effects of 2-pyridylethylamine and dimaprit on nasal symptoms. Both drugs were applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Results show (A) sneezing and (B) nasal rubbing induced by 2pyridylethylamine, and (C) sneezing and (D) nasal rubbing induced by dimaprit. Wild-type mice (open columns); H1 receptor-deficient mice (hatched columns). Each column and vertical bar shows the mean F S.E.M. of 10 experiments. *, **: Significantly different from saline-treated control group at P < 0.05 and P < 0.01, respectively.
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R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
3. Results 3.1. Changes in nasal symptoms after histamine instillation In wild-type mice, histamine caused increases in sneezing and nasal rubbing in a dose-dependent manner, and significant increases in both symptoms were observed at doses of 0.05 and 0.5 Ag/site. However, no observable effects were noted even at a dose of 0.5 Ag/site in histamine H1 receptor-deficient mice (Fig. 1). 3.2. Effects of histamine H1 and H2 receptor agonists on nasal symptoms As shown in Fig. 2, the histamine H1 receptor agonist 2-pyridylethylamine caused significant sneezing and nasal rubbing at doses of 0.5 and 5 Ag/site in wild-type mice. On the other hand, no effect was observed in histamine H1 receptor-deficient mice at a dose of 5 Ag/site. The H2 receptor agonist dimaprit caused no significant increase in either nasal symptom even at a dose of 5 Ag/site in wild-type mice.
Table 1 Effects of histamine H1 and H2 receptor antagonists on histamineinduced nasal symptoms in wild-type mice Drugs Control (histamine 0.5 Ag/site) Histamine + chlorpheniramine Histamine + epinastine Histamine + cimetidine Histamine + famotidine
Dose Sneezing (mg/kg) – 1 3 10 1 3 10 10 30 100 10 30 100
Nasal rubbing
4.7 F 0.6
28.4 F 3.5
3.3 F 0.7 2.5 F 0.6 * 1.8 F 0.4 * * 2.6 F 0.4 2.1 F 0.5 * 1.2 F 0.2 * * 5.9 F 1.8 4.4 F 1.1 3.8 F 0.5 5.4 F 1.1 5.1 F 0.9 4.6 F 0.5
27.3 F 3.2 17.1 F 1.8 * 12.7 F 2.4 * * 22.2 F 2.1 19.8 F 3.5 16.0 F 3.0 * 24.7 F 3.3 24.2 F 2.7 23.6 F 1.5 28.7 F 2.2 25.0 F 2.2 31.2 F 3.6
Histamine was applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Drugs were given orally 1 h before histamine application. Each value represents the mean F S.E.M. for 10 mice. * Significantly different from control at P < 0.05. ** Significantly different from control at P < 0.01.
Table 2 Effects of simultaneous use of chlorpheniramine and cimetidine or famotidine on histamine-induced sneezing and nasal rubbing in wildtype mice Drugs Chlorpheniramine (1 mg/kg) Chlorpheniramine + cimetidine Chlorpheniramine + famotidine
Dose (mg/kg)
Sneezing
Nasal rubbing
–
4.8 F 0.7
25.5 F 3.2
10 30 100 10 30 100
4.6 F 0.5 3.0 F 0.4 4.5 F 0.9 4.5 F 0.8 5.3 F 1.2 5.1 F 0.8
22.0 F 2.9 23.6 F 2.5 22.7 F 2.5 18.8 F 1.7 22.3 F 3.0 21.6 F 4.0
Histamine was applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Drugs were given orally 1 h before histamine application. Each value represents the mean F S.E.M. for 10 mice.
3.3. Effects of histamine H1 and H2 receptor antagonists on histamine-induced nasal symptoms As shown in Table 1, the histamine H1 receptor antagonist, chlorpheniramine, caused a dose-related inhibition on this response induced by histamine (0.5 Ag/site), and a significant effect was observed at doses of 3 and 10 mg/kg in both responses. Epinastine also inhibited both histamine-induced responses, and significant effects were observed at doses of 3 and 10 mg/ kg (sneezing), and 10 mg/kg (nasal rubbing). On the other hand, the histamine H2 receptor antagonists cimetidine and famotidine showed no inhibitory effect on sneezing and nasal rubbing induced by histamine even at a dose of 100 mg/kg. 3.4. Effects of combination of histamine H1 and H2 receptor antagonists on histamine-induced nasal symptoms The effects of combination of chlorpheniramine and cimetidine or famotidine on histamine-induced nasal symptoms are shown in Table 2. Combined use of chlorpheniramine and cimetidine or famotidine had no effect on this response compared with the effect of chlorpheniramine alone (Table 2).
R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
4. Discussion In the present study, the histamine dose that caused significant sneezing and nasal rubbing was 0.05 Ag/ site in wild-type mice. It is generally accepted that guinea pigs are more sensitive to histamine than other animals such as mice and rats. However, Imamura and Kambara [14] reported that when histamine is applied to the nostrils of guinea pigs, a large dose of 200 Ag/ site is needed to cause a sneezing. Kobayashi et al. [15] also reported that the dose of histamine required to cause remarkable sneezing in guinea pigs is about 50 Ag/site. In rats, Kakimoto et al. [16] reported that the histamine dose causing both sneezing and nasal rubbing was 1000 Ag/site. From these findings, it seems likely that the mouse is the most sensitive animal to nasal symptoms following application of histamine to the nostrils. The H1 agonist 2-pyridylethylamine is also effective in causing nasal symptoms, whereas the H2 agonist dimaprit showed no positive effect in wild-type mice. The potency of 2-pyridylethylamine is 10-fold less than that of histamine in some biological activities. For instance, Durant et al. [17] reported that the agonist activity of 2-pyridylethylamine on the contraction of isolated guinea pig ileum was about 1/20 that of histamine. The same findings were reported by Miyamoto and Nishio [18] in the contraction responsiveness of isolated pig basilar artery. These findings suggested at the time that the same relationship would also be true for nasal symptoms induced by histamine. However, histamine caused no sneezing and nasal rubbing in histamine H1 receptor-deficient mice even at a dose of 0.5 Ag/site. The H1 agonist 2-pyridylethylamine also caused no nasal symptoms in histamine H1 receptor-deficient mice even at a dose of 5 Ag/site. In addition, H1 receptor antagonists such as chlorpheniramine and epinastine inhibited histamine-induced nasal symptoms, but the H2 receptor antagonists cimetidine and famotidine showed no effect in wildtype mice. These results strongly indicated that histamine-induced nasal symptoms in mice occurred through activation of histamine H1 receptors. In allergic reactions using histamine H1 receptor-deficient mice, results similar to those reported here were obtained, indicating that vascular permeability in the conjunctiva in allergic conjunctivitis is entirely regulated through histamine H1 receptors [19].
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Testa et al. [20] reported that cimetidine caused a marked reduction in nasal symptoms and a decrease in the total IgE levels in about 70% of treated patients. Carpenter et al. [11] also reported that when H1 and H2 antagonists were used simultaneously, the immediate reactions to allergens including sneezing were significantly lower than when used H1 antagonist alone. These findings suggested that nasal symptoms in humans are also mediated by histamine H2 receptors. In the present study, however, the H2 antagonists cimetidine and famotidine caused no nasal symptoms in wild-type mice. In addition, the effects of combinated use of H1 and H2 antagonists showed no potentiation compared with use of H1 antagonist alone. From these findings, we concluded that histamine H1 receptors, but not H2 receptors, are involved in histamine-induced nasal symptoms. References [1] Sugimoto M, Sugiyama S, Yanagita N, Ozawa T. Laser high performance liquid chromatography determination of prostaglandins in nasal lavage fluid in allergic rhnitis. Clin Exp Allergy 1994;24:324 – 9. [2] Sugimoto Y, Kawamoto E, Chen Z, Kamei C. A new model of allergic rhinitis in rats by topical sensitization and evaluation of H1-receptor antagonists. Immunopharmacology 2000;48:1 – 7. [3] Naclerio RM, Baroody FM, Togias AG. The role of leukotrienes in allergic rhinitis: a review. Am Rev Respir Dis 1991; 143:S91 – 5. [4] White MV, Kaliner MA. Mediators of allergic rhinitis. J Allergy Clin Immunol 1992;90:699 – 704. [5] Narita S, Asakura K, Kataura A. Effects of thromboxane A2 receptor antagonist (Bay u 3405) on nasal symptoms after antigen challenge in sensitized guinea pigs. Int Arch Allergy Immunol 1996;109:161 – 6. [6] White MV. The role of histamine in allergic diseases. J Allergy Clin Immunol 1990;86:599 – 605. [7] Bachert C. Histamine—a major role in allergy? Clin Exp Allergy 1998;28(S6):15 – 9. [8] Howarth PH, Holgate ST. Comparative trial of two non-sedative H1 antihistamines, terfenadine and astemizole, for hay fever. Thorax 1984;39:668 – 72. [9] Naclerio RM, Togias AG. The nasal allergic reaction: observations on the role of histamine. Clin Exp Allergy 1991; 21(S2):13 – 9. [10] Kirkegaard J, Secher C, Borum P, Mygind N. Inhibition of histamine-induced nasal symptoms by the H1 antihistamine chlorpheniramine maleate. Br J Dis Chest 1983;77:113 – 22. [11] Carpenter GB, Bunker-Soler AL, Nelson HS. Evaluation of combined H1- and H2-receptor blocking agents in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 1983;71:412 – 7.
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[12] Brooks CD, Butler D, Metzler C. Effect of H2 blockade in the challenged allergic nose. J Allergy Clin Immunol 1982;70: 373 – 6. [13] Inoue I, Yanai K, Kitamura D, Taniuchi I, Kobayashi T, et al. Impaired locomoter activity and exploratory behavior in mice lacking histamine H1 receptors. Proc Natl Acad Sci U S A 1996;93:13316 – 20. [14] Imamura T, Kambara T. Substance P as a potent stimulator of sneeze responses in experimental allergic rhinitis of guinea pigs. Agents Actions 1992;37:245 – 9. [15] Kobayashi T, Ikeue T, Ito T, Ikeda A, Murakami M, et al. Short-term exposure to diesel exhaust induces nasal mucosal hyperresponsiveness to histamine in guinea-pigs. Fundam Appl Toxicol 1997;38:166 – 72. [16] Kakimoto M, Sugimoto Y, Harada M, Kobayashi Y, Okuma C,
[17]
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et al. Effects of Fujibitol, a remedy for nasal symptoms, on experimental allergic rhinitis in rats. Biol Pharm Bull 2000; 23:1055 – 8. Durant GJ, Ganellin CR, Parsons ME. Chemical differentiation of histamine H1- and H2-receptor agonists. J Med Chem 1975;18:905 – 9. Miyamoto A, Nishio A. Characterization of histamine receptors in isolated pig basilar artery by functional and radioligand binding studies. Life Sci 1993;53:1259 – 66. Nakahara H, Izushi K, Sugimoto Y, Watanabe T, Kamei C. Vascular permeability in allergic conjunctivitis in mice lacking histamine H1 receptors. Eur J Pharmacol 2000;409:313 – 7. Testa B, Mesolella C, Filippini P, Campagnano N, Testa D, et al. The role of H2 antagonists in perennial allergic rhinitis. Laryngoscope 1993;103:1013 – 9.
Histamine H1 receptors are involved in mouse nasal allergic responses: a demonstration with H1 receptor-deficient mice Ryoji Kayasuga a, Yukio Sugimoto a, Takeshi Watanabe b, Chiaki Kamei a,* a Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
b
Received 12 December 2001; received in revised form 29 January 2002; accepted 4 February 2002
Abstract The role of histamine H1 receptors in nasal allergic symptoms (sneezing and nasal rubbing) were studied using histamine H1 receptor-deficient mice. Intranasal instillation of histamine solution resulted in significant increases in sneezing and nasal rubbing in wild-type mice, whereas no increases were observed in histamine H1 receptor-deficient mice. The histamine H1 receptor agonist 2-pyridylethylamine induced sneezing and nasal rubbing in a dose-dependent manner in wild-type mice, but no such increase was found in histamine H1 receptor-deficient mice. On the other hand, the histamine H2 receptor agonist dimaprit did not increase sneezing and nasal rubbing in wild-type mice. Histamine H1 receptor antagonists such as chlorpheniramine and epinastine significantly inhibited nasal allergic symptoms caused by histamine, but the histamine H2 receptor antagonists cimetidine and famotidine showed no effect. No additional effects were observed by combined use of chlorpheniramine and cimetidine or famotidine compared with cimetidine or famotidine alone. These results suggested that histamine H1 receptors play an important role in nasal allergy symptoms induced by histamine. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Nasal allergic symptoms; Sneezing; Nasal rubbing; Histamine H1 receptor; Histamine
1. Introduction Allergic rhinitis is a chronic inflammatory disease characterized by sneezing, itching, congestion and rhinorrhea in humans [1]. Recently, we reported a chronic allergic rhinitis model in rats showing nasal symptoms such as sneezing and nasal rubbing [2]. The chemical mediators involved in allergic rhinitis are
*
Corresponding author. Tel./fax: +81-86-251-7939. E-mail address: [email protected] (C. Kamei).
thought to be histamine, leukotrienes, prostaglandins, thromboxanes, kinins, etc. [1,3 – 5]. Among these mediators, histamine is a substance that causes an increase in vascular permeability and stimulation of sensory nerves [6,7]. It is well known that actions on sensory nerves precipitate itching and sneezing. On the other hand, histamine H1 receptor antagonists are known to be beneficial in relieving nasal itching, sneezing and rhinorrhea in patients with allergic rhinitis [8,9], and they also significantly inhibited histamine-induced tickling, sneezing and discharge in volunteers [10]. Cimetidine added to conventional histamine H1 receptor antagonists may be of some additive benefit in the treatment of seasonal allergic
1567-5769/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 7 - 5 7 6 9 ( 0 2 ) 0 0 0 1 0 - 3
746
R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
rhinitis [11]. However, one study suggested that application of cimetidine significantly worsened secretion and sneezing as compared to a placebo control in humans [12]. Therefore, the present study was performed to clarify the role of histamine H1 receptors in nasal symptoms using histamine H1 receptor-deficient mice.
sneezing and nasal rubbing movements were counted for 10 min by the method of Sugimoto et al. [2].
2. Materials and methods 2.1. Animals Male histamine H1 receptor-deficient and wild-type mice weighing 15 –22 g were used. Histamine H1 receptor-deficient mice were generated by homologous recombination as described [13] and bred in our laboratory. Male wild-type mice (C57BL/6) were obtained from Japan SLC, Shizuoka. Both strains were housed in a temperature-controlled room at 24 F 2 jC with 55 F 15% humidity and were given food and water ad libitum. 2.2. Reagents Histamine dihydrochloride (Nacalai Tesque, Kyoto, Japan), 2-pyridylethylamine dihydrochloride (kindly provided by Smith Kline and French Laboratories, Welwyn Garden City, Herts, UK) and dimaprit dihydrochloride (kindly provided by Smith Kline and French Laboratories) were used. These drugs were dissolved in saline and administered intranasally. D-Chlorpheniramine maleate (Sigma, St. Louis, MO, USA), epinastine hydrochloride (Bo¨ehringer Ingelheim, Ingelheim, Germany), cimetidine (kindly provided by Smith Kline and French Laboratories) and famotidine (kindly provided by Smith Kline and French Laboratories) were suspended in 5% gum arabic and were administered orally. 2.3. Evaluation of nasal symptoms Before the experiment, the animals were placed into an observation cage (32 22 10 cm) for about 10 min for acclimatization. After nasal instillation of 1 Al of histamine solution into the bilateral nasal cavities, the animals were placed into the observation cage (one animal/cage), and the numbers of
Fig. 1. Sneezing and nasal rubbing induced by histamine in wildtype mice and histamine H1 receptor-deficient mice. Histamine was applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Results show (A) sneezing and (B) nasal rubbing induced by histamine. Wild-type mice (open columns); H1 receptor-deficient mice (hatched columns). Each column and vertical bar shows the mean F S.E.M. of 10 experiments. *, **: Significantly different from saline-treated group at P < 0.05 and P < 0.01, respectively.
R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
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2.4. Effects of drugs on nasal symptoms
2.5. Statistical analysis
In this study, test drugs were administered orally 1 h before nasal instillation of histamine (0.5 Ag/site), and the numbers of sneezing and nasal rubbing movements induced by histamine were counted for 10 min.
Data are presented as means F S.E.M. Statistical analysis was performed by one-way analysis of variance with Dunnett’s test. Probability values less than 0.05 were considered significant.
Fig. 2. Effects of 2-pyridylethylamine and dimaprit on nasal symptoms. Both drugs were applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Results show (A) sneezing and (B) nasal rubbing induced by 2pyridylethylamine, and (C) sneezing and (D) nasal rubbing induced by dimaprit. Wild-type mice (open columns); H1 receptor-deficient mice (hatched columns). Each column and vertical bar shows the mean F S.E.M. of 10 experiments. *, **: Significantly different from saline-treated control group at P < 0.05 and P < 0.01, respectively.
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R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
3. Results 3.1. Changes in nasal symptoms after histamine instillation In wild-type mice, histamine caused increases in sneezing and nasal rubbing in a dose-dependent manner, and significant increases in both symptoms were observed at doses of 0.05 and 0.5 Ag/site. However, no observable effects were noted even at a dose of 0.5 Ag/site in histamine H1 receptor-deficient mice (Fig. 1). 3.2. Effects of histamine H1 and H2 receptor agonists on nasal symptoms As shown in Fig. 2, the histamine H1 receptor agonist 2-pyridylethylamine caused significant sneezing and nasal rubbing at doses of 0.5 and 5 Ag/site in wild-type mice. On the other hand, no effect was observed in histamine H1 receptor-deficient mice at a dose of 5 Ag/site. The H2 receptor agonist dimaprit caused no significant increase in either nasal symptom even at a dose of 5 Ag/site in wild-type mice.
Table 1 Effects of histamine H1 and H2 receptor antagonists on histamineinduced nasal symptoms in wild-type mice Drugs Control (histamine 0.5 Ag/site) Histamine + chlorpheniramine Histamine + epinastine Histamine + cimetidine Histamine + famotidine
Dose Sneezing (mg/kg) – 1 3 10 1 3 10 10 30 100 10 30 100
Nasal rubbing
4.7 F 0.6
28.4 F 3.5
3.3 F 0.7 2.5 F 0.6 * 1.8 F 0.4 * * 2.6 F 0.4 2.1 F 0.5 * 1.2 F 0.2 * * 5.9 F 1.8 4.4 F 1.1 3.8 F 0.5 5.4 F 1.1 5.1 F 0.9 4.6 F 0.5
27.3 F 3.2 17.1 F 1.8 * 12.7 F 2.4 * * 22.2 F 2.1 19.8 F 3.5 16.0 F 3.0 * 24.7 F 3.3 24.2 F 2.7 23.6 F 1.5 28.7 F 2.2 25.0 F 2.2 31.2 F 3.6
Histamine was applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Drugs were given orally 1 h before histamine application. Each value represents the mean F S.E.M. for 10 mice. * Significantly different from control at P < 0.05. ** Significantly different from control at P < 0.01.
Table 2 Effects of simultaneous use of chlorpheniramine and cimetidine or famotidine on histamine-induced sneezing and nasal rubbing in wildtype mice Drugs Chlorpheniramine (1 mg/kg) Chlorpheniramine + cimetidine Chlorpheniramine + famotidine
Dose (mg/kg)
Sneezing
Nasal rubbing
–
4.8 F 0.7
25.5 F 3.2
10 30 100 10 30 100
4.6 F 0.5 3.0 F 0.4 4.5 F 0.9 4.5 F 0.8 5.3 F 1.2 5.1 F 0.8
22.0 F 2.9 23.6 F 2.5 22.7 F 2.5 18.8 F 1.7 22.3 F 3.0 21.6 F 4.0
Histamine was applied to the bilateral nostrils of mice, and the numbers of sneezing and nasal rubbing movements were counted for 10 min. Drugs were given orally 1 h before histamine application. Each value represents the mean F S.E.M. for 10 mice.
3.3. Effects of histamine H1 and H2 receptor antagonists on histamine-induced nasal symptoms As shown in Table 1, the histamine H1 receptor antagonist, chlorpheniramine, caused a dose-related inhibition on this response induced by histamine (0.5 Ag/site), and a significant effect was observed at doses of 3 and 10 mg/kg in both responses. Epinastine also inhibited both histamine-induced responses, and significant effects were observed at doses of 3 and 10 mg/ kg (sneezing), and 10 mg/kg (nasal rubbing). On the other hand, the histamine H2 receptor antagonists cimetidine and famotidine showed no inhibitory effect on sneezing and nasal rubbing induced by histamine even at a dose of 100 mg/kg. 3.4. Effects of combination of histamine H1 and H2 receptor antagonists on histamine-induced nasal symptoms The effects of combination of chlorpheniramine and cimetidine or famotidine on histamine-induced nasal symptoms are shown in Table 2. Combined use of chlorpheniramine and cimetidine or famotidine had no effect on this response compared with the effect of chlorpheniramine alone (Table 2).
R. Kayasuga et al. / International Immunopharmacology 2 (2002) 745–750
4. Discussion In the present study, the histamine dose that caused significant sneezing and nasal rubbing was 0.05 Ag/ site in wild-type mice. It is generally accepted that guinea pigs are more sensitive to histamine than other animals such as mice and rats. However, Imamura and Kambara [14] reported that when histamine is applied to the nostrils of guinea pigs, a large dose of 200 Ag/ site is needed to cause a sneezing. Kobayashi et al. [15] also reported that the dose of histamine required to cause remarkable sneezing in guinea pigs is about 50 Ag/site. In rats, Kakimoto et al. [16] reported that the histamine dose causing both sneezing and nasal rubbing was 1000 Ag/site. From these findings, it seems likely that the mouse is the most sensitive animal to nasal symptoms following application of histamine to the nostrils. The H1 agonist 2-pyridylethylamine is also effective in causing nasal symptoms, whereas the H2 agonist dimaprit showed no positive effect in wild-type mice. The potency of 2-pyridylethylamine is 10-fold less than that of histamine in some biological activities. For instance, Durant et al. [17] reported that the agonist activity of 2-pyridylethylamine on the contraction of isolated guinea pig ileum was about 1/20 that of histamine. The same findings were reported by Miyamoto and Nishio [18] in the contraction responsiveness of isolated pig basilar artery. These findings suggested at the time that the same relationship would also be true for nasal symptoms induced by histamine. However, histamine caused no sneezing and nasal rubbing in histamine H1 receptor-deficient mice even at a dose of 0.5 Ag/site. The H1 agonist 2-pyridylethylamine also caused no nasal symptoms in histamine H1 receptor-deficient mice even at a dose of 5 Ag/site. In addition, H1 receptor antagonists such as chlorpheniramine and epinastine inhibited histamine-induced nasal symptoms, but the H2 receptor antagonists cimetidine and famotidine showed no effect in wildtype mice. These results strongly indicated that histamine-induced nasal symptoms in mice occurred through activation of histamine H1 receptors. In allergic reactions using histamine H1 receptor-deficient mice, results similar to those reported here were obtained, indicating that vascular permeability in the conjunctiva in allergic conjunctivitis is entirely regulated through histamine H1 receptors [19].
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Testa et al. [20] reported that cimetidine caused a marked reduction in nasal symptoms and a decrease in the total IgE levels in about 70% of treated patients. Carpenter et al. [11] also reported that when H1 and H2 antagonists were used simultaneously, the immediate reactions to allergens including sneezing were significantly lower than when used H1 antagonist alone. These findings suggested that nasal symptoms in humans are also mediated by histamine H2 receptors. In the present study, however, the H2 antagonists cimetidine and famotidine caused no nasal symptoms in wild-type mice. In addition, the effects of combinated use of H1 and H2 antagonists showed no potentiation compared with use of H1 antagonist alone. From these findings, we concluded that histamine H1 receptors, but not H2 receptors, are involved in histamine-induced nasal symptoms. References [1] Sugimoto M, Sugiyama S, Yanagita N, Ozawa T. Laser high performance liquid chromatography determination of prostaglandins in nasal lavage fluid in allergic rhnitis. Clin Exp Allergy 1994;24:324 – 9. [2] Sugimoto Y, Kawamoto E, Chen Z, Kamei C. A new model of allergic rhinitis in rats by topical sensitization and evaluation of H1-receptor antagonists. Immunopharmacology 2000;48:1 – 7. [3] Naclerio RM, Baroody FM, Togias AG. The role of leukotrienes in allergic rhinitis: a review. Am Rev Respir Dis 1991; 143:S91 – 5. [4] White MV, Kaliner MA. Mediators of allergic rhinitis. J Allergy Clin Immunol 1992;90:699 – 704. [5] Narita S, Asakura K, Kataura A. Effects of thromboxane A2 receptor antagonist (Bay u 3405) on nasal symptoms after antigen challenge in sensitized guinea pigs. Int Arch Allergy Immunol 1996;109:161 – 6. [6] White MV. The role of histamine in allergic diseases. J Allergy Clin Immunol 1990;86:599 – 605. [7] Bachert C. Histamine—a major role in allergy? Clin Exp Allergy 1998;28(S6):15 – 9. [8] Howarth PH, Holgate ST. Comparative trial of two non-sedative H1 antihistamines, terfenadine and astemizole, for hay fever. Thorax 1984;39:668 – 72. [9] Naclerio RM, Togias AG. The nasal allergic reaction: observations on the role of histamine. Clin Exp Allergy 1991; 21(S2):13 – 9. [10] Kirkegaard J, Secher C, Borum P, Mygind N. Inhibition of histamine-induced nasal symptoms by the H1 antihistamine chlorpheniramine maleate. Br J Dis Chest 1983;77:113 – 22. [11] Carpenter GB, Bunker-Soler AL, Nelson HS. Evaluation of combined H1- and H2-receptor blocking agents in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 1983;71:412 – 7.
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