Histamine H₃‐receptors inhibit cholinergic neurotransmission in guinea‐pig airways

The histamine H 3 ‐agonist (R)−α‐methylhistamine (α‐MeHA) caused a dose‐dependent inhibition of vagally‐mediated contraction of a guinea‐pig tracheal tube preparation but did not alter tracheal contraction induced by exogenously‐applied acetylcholine. Blockade of H 1 ‐ and H 2 ‐histamine receptors, and α‐ and β‐adrenoceptors failed to prevent the inhibitory effect of α‐MeHA, whereas the specific H 3 ‐antagonist thioperamide prevented the effect of α‐MeHA on tracheal contraction. In the presence of H 1 ‐ and H 2 ‐receptor antagonists, histamine also inhibited vagally‐mediated tracheal contraction. The inhibitory effect of α‐MeHA was greater with preganglionic (vagus nerve) stimulation than with postganglionic stimulation by electrical field stimulation, suggesting that H 3 ‐receptors are localized both to cholinergic ganglia and to post‐ganglionic nerve‐endings. Our results suggest that H 3 ‐receptors exist on the vagus nerve which modulate cholinergic neurotransmission in the airways.