SELECTIVE DESENSITIZATION OF 5-HYDROXYTRYPTAMINE 2A RECEPTOR-MEDIATEDCONTRACTION IN GUINEA-PIG TRACHEA

5-Hydroxytryptamine (serotonin, 5-HT) contracts the guinea pig trachea through stimulation of 5-HT2A receptors, an effect previously reporte d to rapidly desensitize. The present studies were designed to examine further the putative desensitization to serotonin. In vitro studies i nvestigating functional desensitization of the guinea pig tracheal 5-H T2A receptor documented that 5-HT (3 x 10(-7) M) significantly (50%) b ut incompletely reduced subsequent tracheal maximal contraction to 5-H T. In contrast, an equieffective concentration of carbamylcholine (3 x 10(-8) M) did not reduce guinea pig tracheal contraction to 5-HT. Fur thermore, 5-HT (3 x 10(-7) M) did not diminish tracheal contraction to carbamylcholine. These data indicate that 5-HT can selectively desens itize guinea pig tracheal contraction to 5-HT. In addition, 5-HT-induc ed contraction but not carbamylcholine-induced contraction in guinea p ig trachea declined over time, an effect that was more pronounced at h igh concentrations of 5-HT (1 x 10(-6) and 1 x 10(-5) M). Inhibitors o f mechanisms that oppose contractility to 5-HT (5-HT-induced relaxatio n, uptake of 5-HT, or metabolism of 5-HT) did not reverse the decline in contraction to 5-HT (1 x 10(-5) M). The decline in fi-HT-induced co ntraction was most rapid in the guinea pig trachea and less so in the rat jugular vein and rat aorta, two preparations in which 5-HT induced contraction also occurred via activation of 5-HT2A receptors. These s tudies suggest that 5-HT can functionally and selectively desensitize the 5-HT2A receptor in guinea pig trachea, an effect not likely to be related to opposing actions of 5-HT or reduction in concentration of 5 -HT.