Selectlve desensitization of 5-hydroxytryptamine 2A receptor mediated contraction in guinea pig trachea

Abstract

5-Hydroxytryptamine (serotonin, 5-HT) contracts the guinea pig trachea through stimulation of 5-HT2A receptors, an effect previously reported to rapidly desensitize. The present studies were designed to examine further the putative desensitization to serotonin. In vitro studies investigating functional desensitization of the guinea pig tracheal 5-HT2A receptor documented that 5-HT (3 × 10−7 M) significantly (50%) but incompletely reduced subsequent tracheal maximal contraction to 5-HT. In contrast, an equieffective concentration of carbamylcholine (3 × 10−8 M) did not reduce guinea pig tracheal contraction to 5-HT. Furthermore, 5-HT (3 × 10−7 M) did not diminish tracheal contraction to carbamylcholine. These data indicate that 5-HT can selectively desensitize guinea pig tracheal contraction to 5-HT. In addition, 5-HT-induced contraction but not carbamylcholine-induced contraction in guinea pig trachea declined over time, an effect that was more pronounced at high concentrations of 5-HT (1 × 10−6 and 1 × 10−5 M). Inhibitors of mechanisms that oppose contractility to 5-HT (5-HT-induced relaxation, uptake of 5-HT, or metabolism of 5-HT) did not reverse the decline in contraction to 5-HT (1 × 10−5 M). The decline in 5-HT-induced contraction 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 studies 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.Key words: phosphatidylinositol hydrolysis, receptor desensitization, smooth muscle.