A paradox: the 5-HT2-receptor antagonist ketanserin restores the 5-HT-induced contraction depressed by methysergide in large coronary arteries of calf. Allosteric regulation of 5-HT2-receptors.

Methysergide depresses the contractile effects of 5-hydroxytryptamine (5-HT) in bovine large coronary arteries devoid of endothelium. The IC50 of methysergide for depression of the response to 5-HT was (-log mol/l) 9.8. A low sensitivity contractile effect of 5-HT was not influenced by 1-1,000 nmol/l methysergide. The maximum force of this residual response is approximately 1/3 of the maximum force elicited by 5-HT in the absence of methysergide. Ketanserin restored the 5-HT-induced contraction depressed by methysergide. In the presence of 0.1 mumol/l ketanserin, methysergide caused depression of the 5-HT-induced effects with an IC50 (-log mol/l) of 6.5 without affecting the residual response. We propose that methysergide depresses 5-HT-induced contractions by acting on an allosteric site. The effect of binding of methysergide to the allosteric site would lead to a conformational change of the 5-HT2-receptor, thereby only allowing the production of a residual 5-HT-induced contraction. Ketanserin competes with high affinity not only with 5-HT for the 5-HT2-receptor but also with methysergide for the allosteric site, thus shifting the receptor back into its original conformation. The affinity estimate of ketanserin for the allosteric site yielded a KB (-log mol/l) of 10.3. Ketanserin (1-1,000 nmol/l) antagonized the contractile effects of 5-HT with a potency expected from its affinity for 5-HT2-receptors (-log KB, mol/l 9.4). However, micromolar concentrations of ketanserin antagonized the effects of 5-HT less than expected from its affinity for 5-HT2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)