The thromboxane A2 antagonist, GR32191 (Lumley et al., this meeting) was tested as an inhibitor of platelet
aggregation in the guinea-pig and compared with another Tx-antagonist, AH23848 (Brittain
et al, 1985). Guinea-pigs were dosed with AH23848 or GR32191 at 0.01-1.0mg/kg. At
intervals, blood was taken and PRP was prepared for ex vivo aggregation studies. Collagen
concentrations causing half maximal aggregation (IC50) were calculated for test and vehicle-dosed groups. Inhibition was expressed as a
concentration ratio (IC50 test/IC50 vehicle). For in vivo studies, 111In-labelled platelets (12μCi, 200μl) were injected into anaesthetised guinea-pigs
and 24 hrs later oral doses of AH23848 or GR32191 (0.01-1.0mg/kg) or indomethacin
(5mg/kg) were given. After one hour, blood was taken for platelet and radioactivity
counting. The carotid artery was exposed under anaesthesia and a current of 2mA was
applied for 60 sec. After 90 min, 1cm of the damaged and contralateral carotid vessels
were removed for gamma-counting. Inhibition of accumulation of platelets on the injured
artery was measured by comparison with the undamaged contralateral artery. Numbers
of platelets deposited were calculated from the radioactivity of each section of artery
and the radioactivity and platelet count in the blood. Oral doses of AH23848 or GR32191
inhibited ex vivo platelet aggregation induced by collagen. Maximum inhibition occurred
one hour after dosing, and was still present at 6 hours for AH23848 (l.Omg/kg) and
GR32191 (0.3mg/kg). GR32191 and AH23848 were active in vivo causing inhibition of
platelet deposition at doses of 0.01-lmg/kg. The maximum inhibition of deposition
was 58% for AH23848 (0.1mg/kg) and 63% for GR32191 (0.1mg/kg), with 50% inhibition
at 0.02mg/kg for both. Indomethacin (5mg/kg p.o.) caused maximum inhibition of 58%
at 5mg/kg p.o. suggesting that this represents the total thromboxane involvement in
platelet deposition. GR32191 and AH23848 are thromboxane A2 antagonists with antithrombotic activity after oral dosing to guinea-pigs.
Brittain R.T. et al Circulation, 72, 1208-1218, 1985.
