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
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.