Kinetic characterization of 5-hydroxytryptamine receptor desensitization in isolated guinea-pig trachea and rabbit aorta

Desensitization of the contractile response mediated by the 5-hydroxytryptamine₂ (5-HT₂) receptor in the isolated guinea-pig trachea and rabbit aorta is a time-dependent process and therefore it has been characterized by an apparent rate constant obtained from a kinetic analysis. Under similar conditions, desensitization of the response in the trachea is 7-fold faster than in the aorta. Desensitization is homologous and reversible and is not affected by inhibition of neuronal and extraneuronal uptake, monoamine oxidase activity, alpha₁ adrenergic, cholinergic muscarinic or histamine H₁ receptors. Desensitization does not depend on removal of epithelium from the trachea or endothelium and adventitia from the aorta or on the release of a stable relaxant factor. It is also not affected by the removal of extracellular Ca⁺⁺, which is needed for tonic contraction. The dependence of desensitization on agonist concentration, number of receptors and the intrinsic activity of the agonist was determined. The observed values of the rate constants for desensitization and of the peak tension (T peak) in trachea show a saturable dependence on the concentration of 5-HT, indicating that occupancy of the 5-HT₂ receptor is needed for desensitization. The less efficacious agonists, N-methyl serotonin, dimethyltryptamine, quipazine, 5-methoxytryptamine, 5-methyltryptamine, 5-methoxy dimethyltryptamine, 4-hydroxytryptamine and bufotenine induce significantly slower desensitization than 5-HT. A 25 to 75% reduction in 5-HT₂ receptor number by alkylation had no effect on the observed rate constants for desensitization. This work demonstrates that desensitization of the 5-HT₂ receptor is a time- and tissue-dependent process that depends on the occupancy of the receptor but does not depend on the number of receptors Desensitization depends on intrinsic activity but a quantitative relationship between the observed rate constant for desensitization and intrinsic activity could not be clearly demonstrated.