Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood...

Human blood platelets display alpha2-adrenergic receptors, which promote platelet aggregation and inhibit the adenylate cyclase. We investigated the effects of the antihypertensive agent clonidine and its analogue para-aminoclonidine on this receptor in the intact human platelet to determine their pharmacological effects and their ability to bind to the receptor by radioligand displacement. Both agents potentiated platelet aggregation induced by a submaximal concentration of ADP. Epinephrine-induced aggregation, on the other hand, was antagonized by clonidine and para-aminoclonidine in a dose-dependent fashion. Both agents inhibited the accumulation of cyclic AMP in platelets exposed to prostaglandin E1 and a phosphodiesterase inhibitor, but to a lesser extent than the inhibition caused by epinephrine. Both antagonized this excess inhibitory action of epinephrine. Clonidine and para-aminoclonidine blocked the binding of [3H]yohimbine (a selective alpha 2-adrenergic antagonist) to intact platelets with half-maximal effects at 0.3 and 0.7 microM, respectively. No evidence for the existence of a second class of binding sites with high affinity for clonidine was seen in intact platelets, either by this technique or by direct binding of [3H]clonidine. It is concluded that these two agents are partial agonists for the alpha 2-adrenergic receptors on blood platelets and that this receptor exists predominantly in the low-affinity state in the intact cell.