Pharmacological pleiotropism of the human recombinant α 1A ‐adrenoceptor: implications for α 1 ‐adrenoceptor classification

Three fully‐defined α 1 ‐adrenoceptors (α 1A , α 1B and α 1D ) have been established in pharmacological and molecular studies. A fourth α 1 ‐adrenoceptor, the putative α 1L ‐adrenoceptor, has been defined in functional but not molecular studies, and has been proposed to mediate contraction of human lower urinary tract tissues; its relationship to the three fully characterized α 1 ‐adrenoceptors is not known. In the present study, binding affinities were estimated by displacement of [ 3 H]‐prazosin in membrane homogenates of Chinese hamster ovary (CHO‐K1) cells stably expressing the human α 1A ‐, α 1B ‐ and α 1D ‐adrenoceptors and were compared with affinity estimates obtained functionally in identical cells by measuring inhibition of noradrenaline (NA)‐stimulated accumulation of [ 3 H]‐inositol phosphates. For the α 1A ‐adrenoceptor, binding studies revealed a pharmacological profile typical for the classically defined α 1A ‐adrenoceptor, such that prazosin, RS‐17053, WB4101, 5‐methylurapidil, Rec15/2739 and S‐niguldipine all displayed subnanomolar affinity. A different profile of affinity estimates was obtained in inositol phosphates accumulation studies: prazosin, WB4101, 5‐methylurapidil, RS‐17053 and S‐niguldipine showed 10 to 40 fold lower affinity than in membrane binding. However, affinity estimates were not ‘frameshifted’, as tamsulosin, indoramin and Rec15/2739 yielded similar, high affinity estimates in binding and functional assays. In contrast, results from human α 1B ‐ and α 1D ‐adrenoceptors expressed in CHO‐K1 cells gave antagonist affinity profiles in binding and functional assays that were essentially identical. A concordance of affinity estimates from the functional (inositol phosphates accumulation) studies of the α 1A ‐adrenoceptor in CHO‐K1 cells was found with estimates published recently from contractile studies in human lower urinary tract tissues (putative α 1L ‐adrenoceptor). These data show that upon functional pharmacological analysis, the cloned α 1A ‐adrenoceptor displays pharmacological recognition properties consistent with those of the putative α 1L ‐adrenoceptor. Why this profile differs from that obtained in membrane binding, and whether it explains the α 1L ‐adrenoceptor pharmacology observed in many native tissues, requires further investigation.