Ac. Mackinnon et al., SODIUM MODULATION OF H-3 AGONIST AND H-3 ANTAGONIST BINDING TO ALPHA(2)-ADRENOCEPTOR SUBTYPES, British Journal of Pharmacology, 109(2), 1993, pp. 371-378
1 The alpha2-adrenoceptors on human platelets and neonatal rat lung we
re characterized with the agonist and antagonist ligands [H-3]-adrenal
ine and [H-3]-RS-15385-197 respectively. A correlation of affinities f
or H-3-antagonist binding showed the receptors to be of the alpha2A-(p
latelet) and alpha2B-(neonatal rat lung) adrenoceptor subtypes, wherea
s a correlation of affinities for H-3-agonist binding showed the recep
tors to have similar characteristics (r = 0.88).2 NaCl (100 mM) had no
effect on [H-3]-RS-15385-197 binding in the human platelet, but incre
ased the density of sites labelled with [H-3]-RS-15385-197 in neonatal
rat lung by 52%. NaCl increased the density of sites labelled by [H-3
]-adrenaline in neonatal rat lung, but there was a consequent 3.5 fold
decrease in affinity. In the human platelet, no specific [H-3]-adrena
line binding was observed in the presence of 100 mM NaCl. 3 In the neo
natal rat lung, NaCl had no significant effect on the affinity of praz
osin for [H-3]-RS-15385-197 binding; however, imiloxan affinity was in
creased 13 fold. The affinity of the catecholamines, adrenaline and no
radrenaline was significantly decreased, whereas the imidazolines, oxy
metazoline and UK-14,304 were much less affected. The affinity of praz
osin and imiloxan for [H-3]-adrenaline binding was significantly incre
ased in the presence of 10 and 100 mM NaCl. Conversely, the affinity o
f adrenaline and noradrenaline was decreased in the presence of NaCl,
and there was no change in the affinity of the imidazoline agonists. 4
In the human platelet, NaCl had no effect on the affinity of prazosin
for [H-3]-RS-15385-197 binding but the affinity of imiloxan was signi
ficantly increased. NaCl significantly decreased the affinity of the c
atecholamines adrenaline and noradrenaline, whereas the affinity of UK
-14,304 and oxymatazoline was much less affected. Competition experime
nts with [H-3]-adrenaline in the presence of NaCl in platelets were di
fficult to characterize as there was no specific binding under these c
onditions. 5 The results show that both the alpha2A- and alpha2B-adren
oceptor subtypes are allosterically regulated by Na+, but only the alp
ha2B-subtype showed a significant increase in density. Interestingly,
there is a differential regulation of imidazoline (unchanged) and cate
cholamine (decreased affinity) agonist interactions with these subtype
s. Na+ may therefore critically affect receptor subtype selectivity of
drugs. The implications for receptor subclassification are discussed.