Evidence for allosteric blockade of serotonergic receptors in rabbit thoracic aorta

2-Brom-d-lysergic acid diethylamide (BOL) appeared to behave as either a reversible competitive or noncompetitive antagonist of vascular serotonergic (5-HT2) receptors depending on experimental conditions. This was explored using rabbit thoracic aorta rings mounted in tissue baths for the measurement of isometric contraction. BOL caused concentration-dependent parallel rightward shifts of the 5-HT dose-response curve in untreated aortas but, in addition, caused a marked reduction of maximal response in aortas pretreated with benextramine to inactivate alpha adrenoceptors. Ketanserin behaved as a reversible competitive antagonist in both untreated and benextramine-pretreated aortas. The respective ketanserin pA2 values were 9.08 +/- 0.09 (S.E.M.) and 9.01 +/- 0.04. Ketanserin, 1 x 10(-7) M, reversed completely the reduction of maximal response caused by 1 x 10(-9) M BOL and partially reversed those caused by 1 x 10(-8) and 1 x 10(-7) M BOL. Furthermore, the 5-HT dose-response curve in the presence of 1 x 10(-7) M ketanserin and that in the presence of 1 x 10(-7) M ketanserin plus 1 x 10(-9) M BOL were superimposed. These results are consistent with the conclusion that BOL is a noncompetitive 5-HT2 receptor antagonist. We propose that BOL acts at an allosteric site to convert the 5-HT2 receptor to a low activity state, thus, reducing the maximal response. BOL does not act at the 5-HT2 receptor itself. Ketanserin competes with 5-HT at the 5-HT2 receptor and with BOL at the allosteric site.(ABSTRACT TRUNCATED AT 250 WORDS)