PHARMACOLOGICAL PLEIOTROPISM OF THE HUMAN RECOMBINANT ALPHA(1A)-ADRENOCEPTOR - IMPLICATIONS FOR ALPHA(1)-ADRENOCEPTOR CLASSIFICATION

Citation
Apdw. Ford et al., PHARMACOLOGICAL PLEIOTROPISM OF THE HUMAN RECOMBINANT ALPHA(1A)-ADRENOCEPTOR - IMPLICATIONS FOR ALPHA(1)-ADRENOCEPTOR CLASSIFICATION, British Journal of Pharmacology, 121(6), 1997, pp. 1127-1135
Citations number
29
Categorie Soggetti
Pharmacology & Pharmacy",Biology
ISSN journal
00071188
Volume
121
Issue
6
Year of publication
1997
Pages
1127 - 1135
Database
ISI
SICI code
0007-1188(1997)121:6<1127:PPOTHR>2.0.ZU;2-1
Abstract
1 Three fully-defined al-adrenoceptors (alpha(1A), alpha(1B) and alpha (1D)) have been established in pharmacological and molecular studies. A fourth alpha(1)-adrenoceptor, the putative alpha(1L)-adrenoceptor, h as 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 alpha(1)-adrenocepto rs is not known. 2 In the present study, binding affinities were estim ated by displacement of [H-3]-prazosin in membrane homogenates of Chin ese hamster ovary (CHO-KI) cells stably expressing the human alpha(1A) -, alpha(1B)- and alpha(1D)-adrenoceptors and were compared with affin ity estimates obtained functionally in identical cells by measuring in hibition of noradrenaline (NA)-stimulated accumulation of [H-3]-inosit ol phosphates. 3 For the alpha(1A)-adrenoceptor, binding studies revea led a pharmacological profile typical for the classically defined alph a(1A)-adrenoceptor, such that prazosin, RS-17053, WE 4101, 5-methylura pidil, Rec 15/2739 and S-niguldipine all displayed subnanomolar affini ty. A different profile of affinity estimates was obtained in inositol phosphates accumulation studies: prazosin, WE 4101, 5-methylurapidil, RS-17053 and S-niguldipine showed 10 to 40 fold lower affinity than i n membrane binding. However, affinity estimates were not 'frameshifted ', as tamsulosin, indoramin and Rec 15/2739 yielded similar, high affi nity estimates in binding and functional assays. 4 In contrast, result s from human alpha(1B)- and alpha(1D)-adrenoceptors expressed in CHO-K 1 cells gave antagonist affinity profiles in binding and functional as says that were essentially identical. 5 A concordance of affinity esti mates from the functional (inositol phosphates accumulation) studies o f the alpha(1A)-adrenoceptor in CHO-KI cells was found with estimates published recently from contractile studies in human lower urinary tra ct tissues (putative alpha(1L)-adrenoceptor). These data show that upo n functional pharmacological analysis, the cloned alpha(1A)-adrenocept or displays pharmacological recognition properties consistent with tho se of the putative alpha(1L)-adrenoceptor. Why this profile differs fr om that obtained in membrane binding, and whether it explains the alph a(1L)-adrenoceptor pharmacology observed in many native tissues, requi res further investigation.