Ethanol is a commonly used substance that can significantly influence platelet responses when combined with therapeutic drugs. In in vitro studies, we combined
ethanol with
LY309562, a novel 2,6-disubstituted isoquinolone RGD mimic that competes for
fibrinogen binding to GPIIb/IIIa.
Ethanol inhibits aggregation and secretion, partly by inhibiting
thromboxane A(2) formation. We measured aggregation and secretion of dense granule contents by platelets labeled with [(14)C]
serotonin in plasma from blood anticoagulated with FPRCH(2)Cl (
PPACK). Alone,
LY309562 dose-dependently inhibited aggregation induced by 10 micromol/L
adenosine diphosphate, 1 microg/mL
collagen, 2 micromol/L
U46619 (a
thromboxane A(2) mimetic), or 15 micromol/L
SFLLRN (
protease-activated receptor-1-activating
peptide); inhibition was complete at 1 micromol/L
LY309562 and partial at 0.1 micromol/L (50% inhibitory concentration [IC(50)] 0.19-0.33 micromol/L). Secretion induced by
collagen,
U46619, and
SFLLRN was also inhibited by
LY309562 (IC(50) 0.08-0.31 micromol/L). At inhibitory concentrations of
LY309562,
ethanol (2 or 4 mg/mL) further inhibited responses to
collagen,
U46619, and
SFLLRN (IC(50) for aggregation 0.12-0.16 micromol/L; for secretion 0.04-0.12 micromol/L). Responses of
aspirin-treated platelets to
U46619 were also inhibited, indicating that
ethanol was not acting solely by inhibiting
thromboxane A(2) formation. Because it is likely that our results with
LY309562 are representative of results with other GPIIb/IIIa antagonists, our in vitro data suggest that the concomitant use of GPIIb/IIIa antagonists and consumption of alcoholic beverages may result in further impairment of platelet participation in hemostasis and
thrombosis.