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 microM), 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.