Sodium modulation of 3H‐agonist and 3H‐antagonist binding to α2‐adrenoceptor subtypes

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Abstract
The α2‐adrenoceptors on human platelets and neonatal rat lung were characterized with the agonist and antagonist ligands [3H]‐adrenaline and [3H]‐RS‐15385‐197 respectively. A correlation of affinities for 3H‐antagonist binding showed the receptors to be of the α2A‐(platelet) and α2B‐(neonatal rat lung) adrenoceptor subtypes, whereas a correlation of affinities for 3H‐agonist binding showed the receptors to have similar characteristics (r = 0.88). NaCl (100 mm) had no effect on [3H]‐RS‐15385‐197 binding in the human platelet, but increased the density of sites labelled with [3H]‐RS‐15385‐197 in neonatal rat lung by 52%. NaCl increased the density of sites labelled by [3H]‐adrenaline in neonatal rat lung, but there was a consequent 3.5 fold decrease in affinity. In the human platelet, no specific [3H]‐adrenaline binding was observed in the presence of 100 mm NaCl. In the neonatal rat lung, NaCl had no significant effect on the affinity of prazosin for [3H]‐RS‐15385‐197 binding; however, imiloxan affinity was increased 13 fold. The affinity of the catecholamines, adrenaline and noradrenaline was significantly decreased, whereas the imidazolines, oxymetazoline and UK‐14,304 were much less affected. The affinity of prazosin and imiloxan for [3H]‐adrenaline binding was significantly increased in the presence of 10 and 100 mm NaCl. Conversely, the affinity of adrenaline and noradrenaline was decreased in the presence of NaCl, and there was no change in the affinity of the imidazoline agonists. In the human platelet, NaCl had no effect on the affinity of prazosin for [3H]‐RS‐15385‐197 binding but the affinity of imiloxan was significantly increased. NaCl significantly decreased the affinity of the catecholamines adrenaline and noradrenaline, whereas the affinity of UK‐14,304 and oxymatazoline was much less affected. Competition experiments with [3H]‐adrenaline in the presence of NaCl in platelets were difficult to characterize as there was no specific binding under these conditions. The results show that both the α2A‐ and α2B‐adrenoceptor subtypes are allosterically regulated by Na+, but only the α2B‐subtype showed a significant increase in density. Interestingly, there is a differential regulation of imidazoline (unchanged) and catecholamine (decreased affinity) agonist interactions with these subtypes. Na+ may therefore critically affect receptor subtype selectivity of drugs. The implications for receptor subclassification are discussed.