Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs

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Abstract

We examined the effect of inhaled histamine on citric acid-induced coughs and clarified the role of ionotropic purinergic receptors in the resulting changes. Although the inhalation of 0.1 M citric acid by itself produced only a few coughs in guinea pigs, exposure to histamine, at concentrations of 0.3 to 1 mM, for 2 min concentration dependently increased the number of citric acid-induced coughs. This histamine-induced increase in the number of citric acid-induced coughs was dose dependently and significantly reduced when animals were pretreated with fexofenadine, a histamine H1 receptor antagonist. The histamine-induced increase in the number of citric acid-induced coughs was completely reduced when animals were co-pretreated with 2′,3′-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP, 50 μM), a P2X receptor antagonist, and reactive blue 2, a P2Y receptor antagonist, for 2 min. Furthermore, the ATP-induced increase in the number of citric acid-induced coughs was dose dependently and significantly decreased when animals were pretreated with fexofenadine, at doses of 0.3, 1 and 3 mg/kg, p.o. These results suggest that histamine enhances the excitability of rapidly adapting receptors to tussive stimuli via modulation of ATP release in the airways. Furthermore, ATP might act not only on P2X receptors to directly activate rapidly adapting receptors, but also on P2Y receptors to increase histamine release, indirectly increasing the cough reflex sensitivity.

Introduction

Cough is an important respiratory defense mechanism and one of the most important symptoms of pulmonary disorders. Chronic cough is generally defined as cough persisting for 8 weeks or longer. The morbidity associated with chronic cough in humans is likely to be a product of the enhanced frequency and intensity of coughs that occur as a result of increased sensitivity of the cough reflex. Patients with a variety of pulmonary disorders show an enhanced sensitivity of the cough response to inhaled irritants, and the frequency and intensity of coughs can be increased. The mechanisms by which the sensitivity, spontaneous frequency, and magnitude of coughs are increased in airway disease are poorly understood. Therefore, a better understanding of the pathogenic mechanisms of chronic cough is extremely important for the development of new therapeutic strategies to alleviate this stress.

Increased sensitivity of the afferent nerve endings in the airways mediating cough may be an important patho-mechanism responsible for the coughing of patients suffering from rhino sinusitis. Tatar et al. (Pecova et al., 2001, Plevkova et al., 2005) reported on increased capsaicin-induced cough sensitivity in patients suffering from allergic rhinitis in or out of pollen season. O'Connel et al., 1994, O'Connel et al., 1996 also reported that the sensitivity of capsaicin-induced cough receptors increases during upper respiratory tract infection and decreases with the successful treatment of chronic cough. Curley et al. (1988) showed that decongestant and antihistamine therapy in patients with rhinitis suffering from cough leads to a significant reduction in coughing. Histamine, a biogenic amine synthesized and stored mainly in mast cells and basophils, plays a prominent role in the pathogenesis of allergic rhinitis. The nasal effects of histamine are mediated via interaction with both H1 and H2 receptor subtypes. These effects include sneezing, itching in the nose, nasal discharge, and a decrease in nasal patency (Bachert, 2002). Histamine can stimulate sensory nerve endings and receptors in the nasal mucosa, and also acts indirectly via plasma leakage or pro-inflammatory changes. There is abundant evidence that cough reflex sensitivity is enhanced after intranasal administration of histamine in subjects with or without seasonal allergic rhinitis (Plevkova et al., 2005, Plevkova et al., 2006). Plevkova et al. (2004) further found that this sensitivity is increased in such subjects in contrast to the healthy subjects studied previously. However, the detailed mechanisms that underlie this histamine-induced enhancement of cough reflex sensitivity are not well defined.

We recently demonstrated that although ATP, by itself, does not elicit spontaneous coughs, it may enhance the cough reflex sensitivity (Kamei et al., 2005). Furthermore, stimulation of P2X receptors on rapidly adapting receptors may be required for this ATP-induced enhancement of cough reflex sensitivity (Kamei et al., 2005). It is well known that ATP modulates histamine release from mast cells via P2Y receptors (Schulman et al., 1999). In contrast, some experimental studies have shown that histamine induces the release of ATP from cultured smooth muscle cells and segments of vas deferens via histamine H1 receptors (Tamesue et al., 1998). Although these results strongly suggest that histamine may enhance cough reflex sensitivity by an interaction with an ATP-related mechanism, these interactions are not yet clearly defined.

Therefore, the present study was designed to investigate the effect of inhaled histamine on citric acid-induced coughs, and to clarify the role of ionotropic purinergic receptors in these changes.

Section snippets

Animals

Male Hartley guinea pigs (Tokyo Animal Laboratory Inc., Tokyo, Japan) weighing about 300–350 g were used. The animals were housed in groups of four per cage under a 12-h light–dark cycle with food and water available continuously. These studies were carried out in accordance with the Guidelines for the Use of Laboratory Animals, as adopted by the Committee on the Care and Use of Laboratory Animals of Hoshi University, which is accredited by the Ministry of Education, Science, Sports and Culture.

Effect of histamine on the number of citric acid-induced coughs

A concentration of 0.1 M citric acid was selected to induce coughs, since this concentration by itself produced only a few coughs in guinea pigs (4.0 ± 0.6 coughs/10 min, n = 20). As shown in Fig. 1, exposure to histamine, at concentrations of 0.3 to 1 mM, for 2 min concentration dependently increased the number of citric acid-induced coughs. A significant increase in the number of coughs was observed when animals were exposed to 0.6 and 1 mM of histamine (0.6 mM, pre, 3.5 ± 7.4 coughs/10 min, post,

Discussion

In the present study, we demonstrated that pre-inhalation of histamine concentration dependently and significantly increased the number of citric acid-induced coughs in guinea pigs and that this effect was antagonized by pretreatment with fexofenadine, a histamine H1 receptor antagonist. However, fexofenadine had no effect on the citric acid-induced cough reflex. These results suggest that stimulation of histamine H1 receptors in the airways is required for the histamine-induced enhancement of

Acknowledgements

We are grateful to Sanofi-Aventis for the gift of fexofenadine hydrochloride. We thank Mr. S. Hayashi, Mr. D. Takemura and Miss K. Machida for their excellent technical assistance.

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