DESENSITIZATION OF EPINEPHRINE-INITIATED PLATELET-AGGREGATION DOES NOT ALTER BINDING TO THE ALPHA-2-ADRENERGIC RECEPTOR OR RECEPTOR COUPLING TO ADENYLATE-CYCLASE

  • 1 January 1986
    • journal article
    • research article
    • Vol. 29  (1) , 1-6
Abstract
Several investigators have shown that incubating unstirred platelets with epinephrine blunts subsequent aggregation when the platelets are stirred. Using aspirin-treated platelets, we further characterized this desensitization of .alpha.2-adrenergic receptor-initiated aggregation. Desensitization occurred with a t1/2 of 3-6 min and was maximal at 20-30 min, at which time the initial rate of aggregation and its maximal extent were about half that of control platelets. When we preincubated platelets with epinephrine, and then added phentolamine in block the .alpha.2-receptors, ADP-initiated aggregation occurred normally. Thus, the desensitization of ephinephrine-initiated aggregation was not associated with a generalized impairment of aggregation. At concentrations too low to initiate aggregation, epinephrine is known to potentiate aggregation initiated by other agents. Clonidine also acts at .alpha.2-receptors to potentiate aggregation initiated by other agents, but it does not initiate aggregation by itself. Preincubating clonidine with platelets for 30 min abolished the potentiating effect on ADP-initiated aggregation. Thus, the ability of .alpha.2-receptors to both potentiate and initiate aggregation desensitizes after a brief preincubation with agonist. We performed several types of experiments to investigate the mechanism of this desensitization. Platelet .alpha.2-receptors are coupled to an inhibition of adenylate cyclase. We found, however, that .alpha.2-mediated inhibition of prostaglandin E1-stimulated cAMP accumulation occurred normally in desensitized platelets. Similarly, epinephrine inhibited basal adenylase cyclase activity normally in membranes prepared from desensitized platelets. In membranes prepared from desensitized platelets, epinephrine competed normally for [3H]rauwolscine binding, and this competition was modulated normally by guanine nucleotides. Thus, the properties of the .alpha.2-receptors, as measured in radioligand binding experiments, were unchanged by desensitization. In conclusion, desensitization of .beta.2-adrenergic receptor-mediated aggregation occurs without change in the .alpha.2-adrenergic receptors or in their coupling to an inhibition of adenylate cyclase.