MECHANISM OF EPINEPHRINE-INDUCED PLATELET-AGGREGATION

We report that a genetic polymorphism of the alpha(2)-adrenergic recep tor (A2AR) encoded by chromosome 10 is associated with hypertension an d an increase in epinephrine-mediated platelet aggregation in humans. The mechanism responsible for this heritable contrast in sensitivity t o epinephrine is unknown. We tested our hypothesis that epinephrine-in duced platelet aggregation is mediated by activation of chloride trans port. We measured epinephrine-mediated increases in optical density of gel-filtered platelets suspended in a bicarbonate-buffered physiologi cal salt solution. Compared with platelets incubated in the control bu ffer (130 mmol/L NaCl), platelets incubated with either bumetanide, a Na/K/2Cl cotransport inhibitor; anthracene-9-carboxylic acid, a chlori de channel blocker; or acetazolamide, an agent that blocks ATP-depende nt chloride transport had significantly decreased aggregation response s to epinephrine. When measured fluorometrically, epinephrine signific antly increased intraplatelet chloride concentrations. Chloride-depend ent modifications of epinephrine-induced platelet aggregation were not attributable to changes in A2AR ligand binding characteristics or to the concentration of platelet cAMP. Finally, subthreshold concentratio ns of epinephrine also potentiated thrombin-induced platelet aggregati on, and blockade of chloride transport diminished this synergistic act ion of epinephrine on thrombin-stimulated platelet aggregation. Herita ble differences in epinephrine-mediated platelet aggregation may be at tributable to genetic differences in chloride transport in platelets. Furthermore, because we observed a necessary role for chloride transpo rt in epinephrine-mediated platelet aggregation, pharmacological agent s that block chloride transport, such as diuretics, may provide saluta ry protection against vascular thrombosis in patients with hypertensio n independent of the effect of these drugs on blood pressure.