GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster

Abstract

1. The present study investigated the inhibitory effect of losartan, a type 1 angiotensin II receptor (AT1) antagonist, and of combined treatment with losartan and GR144053, a fibrinogen receptor (GPIIb/IIIa) antagonist, on neointima formation subsequent to vascular injury in the hamster carotid artery. Vascular injury was achieved by a roughened-tip 2F catheter and the neointimal area was measured up to 2 weeeks inducing the injury.

2. Compared to non-treated hamsters (intimal area (IA)/internal elastic laminal area (IELA) ratio = 60.3±5.9%, n=12), losartan dissolved in drinking water (1, 3 and 10 mg kg⁻¹ per day, n=8 each) reduced neointimal area dose-dependently, a significant decrease (IA/IELA=39.7±5.6%) being attained with the highest dose when it was administered from 1 day before injury. However, neointima formation was not prevented even with the highest dose of losartan when the administration was started after injury.

3. When the administration of GR144053 (1.0 mg kg⁻¹ per hour) via an implanted osmotic pump was started 30 min before the injury and continued for the next 2 weeks, no suppression of neointima formation was observed, although platelet aggregation evoked ex vivo by adenosine diphosphate (ADP) at the end of treatment period was efficiently inhibited.

4. In separate experiments in which 5-bromo-2-deoxy-Uridine (BrdU) was used to test smooth muscle cell (SMC) proliferation 1 and 7 days after injury, the ratio of SMC proliferation in the injured area was only slightly decreased by losartan when its administration was started after the injury, despite the marked reduction of SMC proliferation when treatment was started before the injury. Treatment with GR144053 as indicated above also significantly decreased the SMC proliferating index 1 day after the injury.

5. To examine the potential benefit of the coadministration of the GPIIb/IIIa antagonist with the AT1 receptor antagonist, GR144053 (1.0 mg kg⁻¹ per hour) was combined with post-injury treatment with losartan (10 mg kg⁻¹ per day). This markedly reduced the proliferation of SMCs and significantly decreased the neointimal area (IA/IELA=31.2±4.6%) measured 2 weeks following the catheterization.

6. According to the results of a time-dependent study in which GR144053 was given in combination with post injury treatment with losartan for 1, 3, 7 or 14 days, neointima formation could be reduced by treatment with GR144053 for just 7 days.

7. In conclusion, GR144053, a fibrinogen receptor antagonist, enhanced the inhibitory effect of losartan, an AT1 receptor antagonist, on neointima formation in the damaged carotid artery of hamsters.

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