Potentiation by adrenaline of human platelet activation and the inhibition by the alpha-adrenergic antagonist nicergoline of platelet adhesion, secretion and aggregation

Abstract

Adrenaline (1 to 10 microM) can induce the aggregation of human platelets suspended in citrated plasma but does not induce the aggregation of washed human platelets at doses as high as 1 mM, although these platelets respond normally to ADP, PAF-acether, collagen, arachidonic acid, thrombin, the endoperoxide analog U-46619 and the Ca2+ ionophore A23187. Adrenaline (0.5 microM) potentiates the aggregation and secretion induced by all the previous agonists in citrated platelet-rich plasma (cPRP) or in washed platelets. The activation by adrenaline of human platelets is mediated by alpha 2-adrenergic receptors, as demonstrated by inhibition with a series of adrenergic antagonists. The alpha-adrenergic antagonist nicergoline inhibits the activation of human platelets by adrenaline in the following situations: nicergoline inhibits the aggregation and secretion caused by adrenaline in cPRP (IC50 0.22 microM and 0.28 microM respectively); nicergoline inhibits the aggregation and secretion induced by the combination of adrenaline and each aggregating agent listed above in cPRP (IC50 ranging from 0.1 to 2.5 microM) or in washed platelets (IC50 ranging from 0.1 to 0.8 microM); nicergoline inhibits the binding of 3H-yohimbine to washed human platelets (IC50 0.26 microM); the intravenous administration of nicergoline (0.5 mg/kg per day) to patients inhibits significantly the ex vivo response of their platelets to adrenaline in cPRP. High concentrations of nicergoline also inhibit the aggregation and secretion induced by the aggregating agents listed above in cPRP (IC50 range 108 to 670 microM) and in washed platelets (IC50 range 27 to 140 microM) and the adhesion of platelets to collagen-coated surfaces. This latter effect is not mediated through blockade of alpha-adrenoceptors. A possible role of adrenaline in platelet activation in vivo could justify the use of nicergoline (Sermion), an alpha-adrenergic antagonist in combination therapy to prevent arterial thrombosis.

Role of catecholamines in platelet function: pathophysiological and clinical significance

“…This effect is more evident for adrenaline, which potentiates platelet aggregation at very low concentrations in response to a large cluster of agonists that activate the platelets through different receptors and different metabolic pathways: adenosine 5 0 -diphosphate (ADP), PAF, collagen, arginine vasopressin, thrombin and sodium arachidonate [158][159][160][161][162][163][164][165][166][167][168][169][170][171][172][173].…”

“…In humans, adrenaline-induced aggregation is potentiated by platelet exposure to angiotensin II through an effect on Ca 2 availability [250] and subaggregating catecholamine concentrations synergize with subaggregating levels of other agonists (ADP, collagen, arachidonate, thrombin, 5-hydroxytryptamine, arginine vasopressin) to determine a complete platelet response [169,171,172,239,251]. In the same way, activation of PKC by low concentrations of phorbol esters determines full platelet aggregation and secretory response in the presence of subaggregating adrenaline amounts [252].…”

Effect of ?a-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in Type 2 (non-insulin-dependent) diabetes mellitus

“…The conclusions of Takeda et al [1] are supported by the finding that the elevated plasma concentrations of ACTH, cortisol, growth hormone and prolactin that occur during acute hypoglycaemia are unlikely to activate platelets [2][3][4].…”

“…2. Similarly, Lanza et al [4] demonstrated that the concentration for 50% inhibition (ICs0) of an c~-antagonist, nicergoline, for the thrombin-induced aggregation was 60 times greater than that for the aggregation induced by epinephrine with thrombin. In addition, they described similar results with adenosine 5'-diphosphate, collagen, arachidonic acid, platelet activating factor and A23187.…”

Effect of Labetalol on Human Platelet Function

“…Inhibition of platelet activation by adrenergic blocking agents has been demonstrated in a number of previous studies (Bygdeman & Johnsen 1969). Since catecholamine-induced platelet responses are mediated by presynaptic a2-receptors (Alexander et al 1978;Daiguji et al 198 l), non-selective and a2-selective blocking agents interfere with catecholamine effects at low concentrations (OBrien 1963;Mills & Roberts 1967a;Bygdeman & Johnsen 1969;Alexander et al 1978;Hsu et al 1979;Lanza et al 1986). Postsynaptic al-receptor blocking drugs are substantially less potent at inhibiting catecholamine-induced responses (Glusa et al 1979).…”