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.