Allosteric properties of 5-HT2 receptors in tracheal smooth muscle.

5-Hydroxytryptamine (5-HT)-induced contractions were investigated in isolated tracheal smooth muscle of guinea pig and calf. In guinea-pig tracheae, ketanserin reduced to 60% the maximum response to 5-HT, but also shifted the concentration-effect curve for 5-HT to higher 5-HT concentrations, as expected from its affinity for 5-HT2 receptors [pKB = -log KB = 9.6, KB in mol/l]. The concentration effect-data for the depressant effect of ketanserin are closely associated with the curve for occupancy of 5-HT2-receptors by ketanserin. In calf tracheae, ketanserin caused surmountable antagonism of the effects of 5-HT with a pKB of 9.5. Methysergide reduced to 25% the maximum response to 5-HT in guinea-pig tracheae and to 20% in calf tracheae. The methysergide-depressed response to 5-HT was restored by ketanserin to 60% of maximum in guinea-pig tracheae, and to 100% in calf tracheae. The results support for tracheal smooth muscle a model of an allosteric regulation of 5-HT2-receptors which was proposed for arterial smooth muscle by Kaumann and Frenken (this journal 328:295-300, 1985). The model requires that: the 5-HT2 receptor exists in two interconvertible states R in equilibrium R'; 5-HT causes its effects through R; methysergide, by acting on an allosteric site near or on the 5-HT2 receptor, shifts the equilibrium into the inactive state R'; ketanserin competes with 5-HT for the 5-HT2 receptor and with methysergide for the allosteric site, thereby restoring the active state R of the 5-HT2-receptor. All four requirements were experimentally verified in calf trachea.(ABSTRACT TRUNCATED AT 250 WORDS)