Synthetic α-adrenergic agonists are potent α-adrenergic blockers in human platelets

Abstract

ADRENALINE- and noradrenaline-induced aggregation of human platelets^1–3 is blocked by the α-adrenergic blocking agents, dihydroergotamine, phentolamine, phenoxybenzamine and dibenamine^4–6, suggesting the involvement of α-adrenergic receptors. We have demonstrated that adrenaline and noradrenaline inhibit adenylate cyclase (EC 4.6.1.1) in lysates⁷ and particles⁸ of human platelets, an effect also blocked by such α-adrenergic antagonists. Synthetic phenylethylamine and imidazoline derivatives that act as α-adrenergic agonists in various other tissues neither induced primary platelet aggregation nor inhibited adenylate cyclase when added at concentrations up to 100 µM⁹. α-Adrenergic receptors have been identified in human platelets by binding studies using tritiated dihydroergocryptine^10,11 or dihydroergonine^12,13. The sites to which the dihydrogenated ergot alkaloids were bound showed the typical pattern of an α-adrenergic receptor with respect to displacement by adrenergic agonists and antagonists. However, there have been some discrepancies between the binding affinities of some α-adrenergic agonists and their biological efficacies concerning platelet aggregation and inhibition of adenylate cyclase. The α-adrenergic agonist, clonidine, displaced dihydroergocryptine from the binding sites with similar¹⁰ or even a 10-fold higher affinity¹¹ relative to adrenaline, but clonidine (up to 100 µM) was ineffective in inducing primary platelet aggregation and inhibition of adenylate cyclase⁹. Similar dissociation constants were obtained for phenylephrine and noradrenaline in binding studies¹², but in contrast to the natural compound, phenylephrine (up to 100 µM) was unable to induce a biological response⁹. We observed similar discrepancies with methoxamine, xylometazoline and oxymetazoline^12,13. Agents that undergo the primary reaction of high affinity-binding to the receptor but are unable to induce secondary reactions in the form of biological responses should act as antagonists. We have tested this hypothesis and show here that various agents that are potent α-adrenergic agonists in various other systems are α-adrenergic antagonists in human platelets with respect to adrenaline-induced aggregation and inhibition of adenylate cyclase.