Agonist regulation of the human platelet α-adrenergic receptor

Abstract

PROLONGED exposure to drugs or hormones may result in diminished physiological responsiveness which is referred to as tolerance or desensitisation. One mechanism which has been proposed to explain tolerance is a change in the state of tissue receptors following activation by drugs or hormones¹. The receptor desensitisation hypothesis to explain tolerance to the β-adrenergic effects of catecholamines has been particularly well characterised in the frog erythrocyte^1–4. In contrast, the regulation of catecholamine α-adrenergic receptor-mediated responses has been much less extensively investigated. Although the development of rapid desensitisation or tachyphylaxis is not a prominent feature of many α-adrenergic responses, rat parotid cells lose their α-adrenergic mediated potassium secretory response after 2–4 min of (−)adrenaline exposure⁵. Concomitantly, there was a decrease in binding of the α-adrenergic antagonist ³H-dihydroergocryptine to these cells which was thought to represent either a decrease in number or affinity of α-adrenergic receptors. It has been hypothesised that α- as well as β-adrenergic responses in man diminish with chronic exposure to high concentrations of catecholamines⁶. The human platelet would seem to be a useful tissue to investigate this possibility, as catecholamine-induced platelet aggregation is mediated through α-adrenergic receptors. We have recently characterised the human platelet α-adrenergic receptor by ligand binding assay using ³H-dihydroergocryptine and have shown good correlation between binding characteristics and the biochemical and physiological manifestations of α-adrenergic receptor activation⁷. We now report that the human platelet α-adrenergic receptor is subject to ligand regulation as assessed by ³H-dihydroergocryptine binding and that this regulation is reflected in altered physiological function.