Histamine is a mast cell derived mediator of bronchoconstriction. It is believed to exert its effects via histamine H1 receptors located on smooth muscle cell membranes. Very little is known about these receptors. The objective of this proposal is to study the biochemical structure and function of the histamine H1 receptor in human and animal smooth muscle. The hypothesis is that specific histamine receptor abnormalities may contribute to the pathogenesis of airway obstruction in obstructive airway diseases and bronchial hyperreactivity. Abnormal receptor function may be identified through measurement of membrane receptor density and affinity for histamine. Radioligand binding will be used with [3H]pyrilamine in order to quantitate and characterize smooth muscle histamine H1 receptors. A photoaffinity labelling technique using tritiated histamine complexed with a bifunctional heterogeneous photoaffinity label will be used to radioactively label the receptor. The non-radioactive form of this compound competes with [3H]pyrilamine for binding to the histamine receptor in human ileal smooth muscle and pig trachealis muscles. Its H1 antihistaminic activity has been demonstrated in pig tracheal muscle-contraction experiments. The radioactive compound, when incubated with smooth muscle membranes in the presence of strong light is covalently and permanently bound to these membranes. The application of this technique used in conjunction with protein separation by polyacrylamide gel electrophoresis should allow the identification and molecular characterization of animal and human histamine H1 receptors. Radioligand binding and photoaffinity labelling will be used to study histamine H1 receptors in human lung tissue resected during the course of surgery for lung cancer. An attempt will be made to obtain and analyze post mortem lung tissue from persons with chronic bronchitis and asthma. This research had added relevance in view of the recent development of a new class of antihistamine drugs which may have a role in the management of asthma. The proposal may also provide a better understanding of the pathogenesis of anaphylaxis, allergic rhinitis, and urticaria, other diseases in which histamine is believed to play an important causative role.
| Driver, A G; Kukoly, C A; Metzger, W J et al. (1991) Bronchial challenge with adenosine causes the release of serum neutrophil chemotactic factor in asthma. Am Rev Respir Dis 143:1002-7 |
| Driver, A G; Kukoly, C A; Bennett, T E (1989) Expression of histamine H1 receptors on cultured histiocytic lymphoma cells. Biochem Pharmacol 38:3083-91 |
| Driver, A G; Mustafa, S J (1987) Correlation of histamine H1 receptor function and [3H]mepyramine binding in porcine tracheal tissue. Eur J Pharmacol 139:287-95 |
