Regulation of H₁‐receptor coupling and H₁‐receptor mRNA by histamine in bovine tracheal smooth muscle

Pretreatment of bovine tracheal smooth muscle (BTSM) with histamine (1–100 μ M , 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 μ M 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 H 1 ‐receptor (H 1 R) desensitization could be antagonized by mepyramine (an H 1 ‐receptor antagonist, 1 μ M ) but not by cimetidine (an H 2 ‐receptor antagonist, 10 μ M ), indicating that the desensitization occurred via stimulation of histamine H 1 ‐receptors, without evidence for the involvement of histamine H 2 ‐receptors. Indomethacin (10 μ M ) did not block the H 1 R desensitization, suggesting no involvement of prostaglandins. Furthermore, histamine pre‐incubation in calcium free medium still induced a functional uncoupling of H 1 R. GF 109203X, a protein kinase C (PKC) inhibitor, and H‐7, a non‐selective kinase inhibitor, did not antagonize the homologous H 1 R desensitization. The steady‐state level of H 1 R mRNA, assessed by Northern blot analysis, was not affected by prolonged histamine exposure (100 μ M , 0.5, 1, 2, 4, 16 and 24 h). These results suggest that histamine induces desensitization of the H 1 R 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. British Journal of Pharmacology (1998) 123 , 984–990; doi: 10.1038/sj.bjp.0701697