Pretreatment of bovine tracheal smooth muscle (BTSM) with histamine (1–100 μM, 1 h) induced a concentration‐dependent desensitization of the contractile response to subsequently administered histamine, with a reduction of the maximum response of 72±8% (n=5) following pre‐exposure to 100 μM histamine. In contrast, concentration‐response curves to the muscarinic agonist, methacholine were not affected following histamine pretreatment, indicating a homologous desensitization. Furthermore, concentration‐response curves to NaF, a G‐protein activator, were not altered following histamine pre‐incubation.

The histamine H₁‐receptor (H₁R) desensitization could be antagonized by mepyramine (an H₁‐receptor antagonist, 1 μM) but not by cimetidine (an H₂‐receptor antagonist, 10 μM), indicating that the desensitization occurred via stimulation of histamine H₁‐receptors, without evidence for the involvement of histamine H₂‐receptors.

Indomethacin (10 μM) did not block the H₁R desensitization, suggesting no involvement of prostaglandins. Furthermore, histamine pre‐incubation in calcium free medium still induced a functional uncoupling of H₁R.

GF 109203X, a protein kinase C (PKC) inhibitor, and H‐7, a non‐selective kinase inhibitor, did not antagonize the homologous H₁R desensitization.

The steady‐state level of H₁R mRNA, assessed by Northern blot analysis, was not affected by prolonged histamine exposure (100 μM, 0.5, 1, 2, 4, 16 and 24 h).

These results suggest that histamine induces desensitization of the H₁R at the level of the receptor protein, which involves a mechanism independent of PKC, PKA, PKG and calcium influx, suggesting the involvement of a receptor‐specific kinase.