The effects of imidazoline agents on the aggregation of human platelets

Abstract

Abstract Clonidine (2-[(2, 6-dichlorophenyl)amino]-2-imidazoline), an imidazoline α2-adrenoceptor agonist, is known to exert complex effects on human platelet aggregation distinct from those of the catecholamines, which are non-imidazoline α-adrenoceptor agonists. This study has investigated the aggregatory/anti-aggregatory effects of various imidazolines on human platelets. Blood samples were taken from normal volunteers and platelet aggregation was assessed by a turbidimetric method using a Chronolog aggregometer. Noradrenaline (2 μm) and adenosine diphosphate (1 μm) were used as aggregating agents. The results showed that, with the exception of moxonidine, all of the imidazoline agents used (with or without α2-adrenoceptor activity) were able to inhibit noradrenaline-induced platelet aggregation. Compared with the non-imidazoline α2-adrenergic antagonist, yohimbine, the rank order of potency was: efaroxan (IC50 = 3.07 times 10−8  m) > idazoxan (IC50 = 1.74 times 10−7  m) > tolazoline (IC50 = 3.90 times 10−7  m) > clonidine (IC50 = 1.49 times 10−6  m) ≅ antazoline (IC50 = 1.77 times 10−6  m) > yohimbine (IC50 = 3.19 times 10−6  m) > rilmenidine (IC50 = 1.27 times 10−5  m) > moxonidine (IC50 > 10−4  m). Clonidine-displacing substance (CDS), a putative endogenous ligand at imidazoline receptors, was found to inhibit noradrenaline-induced platelet aggregation. Harmane, norharmane and agmatine, putative candidates for the active principle of CDS, had no effect on noradrenaline-induced platelet aggregation. In contrast to noradrenaline-induced aggregation, ADP-induced platelet aggregation was neither potentiated nor inhibited by the imidazoline agents, with the exceptions of clonidine and moxonidine. In conclusion, most imidazoline agents effectively inhibit noradrenaline-induced human platelet aggregation. The lack of effect of moxonidine and the proposed endogenous ligands suggested this effect was mediated by an ‘atypical’ non-adrenoceptor imidazoline-binding site. The results indicated an anti-aggregatory role of imidazoline compounds on noradrenaline-induced human platelet aggregation. In addition, CDS might be an endogenous modulator that prevented platelet hyper-reactivity to catecholamine stimulation.