Interconversion into a low active state protects vascular 5-HT2-receptors against irreversible antagonism by phenoxybenzamine.

Recently, Kaumann and Frenken (1985) proposed an allosteric model of vascular 5-HT2-receptors. We now present experiments in both bovine coronary and pulmonary artery, using the method of irreversible receptor occlusion, that support and extend the model. 1 Phenoxybenzamine was found to cause irreversible antagonism of the effects of 5-hydroxytryptamine (5-HT). Maximal contractile effects induced by 5-HT were depressed and, with further receptor occlusion, concentration-effect curves for 5-HT became biphasic. The high-sensitivity and the low-sensitivity component of the curve for 5-HT consisted of quickly and slowly developing contractions, respectively. 2 Biphasic concentration-effect curves for 5-HT after receptor occlusion were shifted to the right in non-parallel manner by ketanserin and became monophasic with an unexpected partial restoration of maximal responses to 5-HT. The magnitude of the shift of the partially restored concentration-effect curve for 5-HT by ketanserin after receptor occlusion by phenoxybenzamine is consistent with an interaction of ketanserin with 5-HT2-receptors. 3 Preincubation with methysergide before phenoxybenzamine-treatment followed by washout of both drugs, and subsequent incubation with ketanserin completely prevented a depression of 5-HT-induced effects by phenoxybenzamine. 4 Estimates for the equilibrium dissociation constant of 5-HT for the 5-HT2-receptor derived from fast developing contractions range from 0.1 μmol/l to 0.4 μmol/l. 5 The results are consistent with a model of two interconvertible states of the 5-HT2-receptor. Phenoxybenzamine occludes the 5-HT2-receptor in the R-state but not in the R′-state. The low active R′-state of the 5-HT2-receptor appears to pre-exist in the absence of drugs and is not affected by phenoxybenzamine. By converting R′ into R ketanserin restores partially the response to 5-HT after occlusion of the R-state by phenoxybenzamine. Methysergide prevents the 5-HT2-receptor occlusion induced by phenoxybenzamine indirectly by favouring isomerisation into the R′-state.