Heterogeneity of α2‐adrenoceptors in rat cortex but not human platelets can be defined by 8‐OH‐DPAT, RU 24969 and methysergide

Abstract

1 Saturation experiments indicated that [³H]-yohimbine binding was specific, saturable and labelled a single population of sites in rat cerebral cortex (K_d 5.3 ± 0.9 nm, B_max 121 ± 10 fmol mg⁻¹ protein) and human platelets (K_d 0.7 ± 0.1 nm, B_max 152 ± 10 fmol mg⁻¹ protein). 2 The α₂-adrenoceptor antagonists, yohimbine, rauwolscine, WY 26703, idazoxan and BDF 6143 displaced [³H]-yohimbine binding to each tissue in a simple manner, with high affinity and Hill slopes close to unity. 3 The α₁-adrenoceptor agonist, oxymetazoline and the antagonist prazosin inhibited the binding of [³H]-yohimbine to rat cortex in a complex manner consistent with an interaction at more than one site. However, indoramin and WB 4101 only appeared to interact with one site. In contrast, in human platelets, all antagonists gave rise to monophasic displacement curves with Hill slopes close to unity suggesting a single site of interaction. 4 The 5-hydroxytryptamine (5-HT) receptor ligands, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), RU 24969, and methysergide inhibited the binding of [³H]-yohimbine to rat cortex with high and low affinity, consistent with an interaction with two populations of binding sites. However, inhibition of [³H]-yohimbine binding to human platelets suggested a single site of interaction. The low affinity of 5-HT, 5-carboxyamidotryptamine (5-CT) and dipropyl-5-CT indicated that [³H]-yohimbine was not labelling a 5-HT₁-like site in rat cortex. 5 The ability of 8-OH-DPAT, RU 24969 and methysergide in addition to prazosin and oxymetazoline to differentiate [³H]-yohimbine binding provides additional pharmacological evidence for heterogeneity within rat cortical α₂-adrenoceptors. However, if the two sites in rat cortex that are differentiated by the 5-HT ligands represent α_2A- and α_2B-adrenoceptor subtypes as defined by prazosin and oxymetazoline, then they do not correspond to the population of sites in human platelets. As receptor classification should be linked to affinity of drugs rather than tissue distribution, the current classification of α₂-adrenoceptor subtypes does not appear to be satisfactory.