In vitro and in vivo effects of UP 269-6, a new potent orally active nonpeptide angiotensin II receptor antagonist, on vascular smooth muscle cell proliferation

1 The present studies were designed to measure the affinity of UP 269-6, a newly developed angiotensin AT1 receptor antagonist, for vascular AT1 receptors from normotensive and hypertensive rats and to investigate in vitro, its effects on angiotensin II (AII)-induced hyperplasia and hypertrophy of vascular smooth muscle cells (VSMC). In addition the in vivo effects of UP 269-6 on neointimal proliferation in a carotid artery balloon injury in normotensive rats were also investigated. 2 UP 269-6 selectively inhibited [125I]-Sar1-Ile8-AII binding to vascular AT1 receptors present on VSMC derived from normotensive Wistar rat and from SHR (Ki= 16.6 ± 3.6 nM and 7.5 ± 2.0 nM, respectively). In comparison, losartan and its metabolite, EXP 3174, inhibited [125I-Sar1-Ile8-AII binding to vascular AT1 receptors derived from both cell models with Ki values slightly lower (losartan) and higher (EXP 3174), respectively, than that of UP 269-6. 3 AII (1 μM) induced a weak and variable hyperplastic response (4 to 32% increase in cell number) in Wistar rat VSMC after 96 h. 4 AII (1 μM) induced a time-dependent increase in cell number in VSMC from SHR. UP 269-6 inhibited concentration-dependently this effect with an IC50 value of 159 ± 58 nM. Losartan was clearly less potent and EXP 3174 showed nearly the same inhibitory potency, compared to UP 269-6. UP 269-6 (1 μm) inhibited nearly completely the action of AII. 5 AII (500 nM) caused maximal stimulation of protein synthesis in Wistar rat VSMC (117 ± 36%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 28 ± 6 nM, 3504 ± 892 nM and 21±3 nM, respectively. 6 AII (50 nM) induced maximal stimulation of protein synthesis in SHR VSMC (237 ± 67%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 16 ± 3 nM, 282± 122 nM and 3.3 ± 1.0 nM, respectively. 7 UP 269-6 (75 mg kg−1 day−1) administered orally in the diet for 20 days induced a 38% reduction in neointimal area and a 36% reduction in neointima/media ratio associated with the intimal thickening induced by carotid artery balloon injury. 8 In conclusion, UP 269-6 was shown to be a potent antiproliferative agent both in vitro on AII-induced hyperplasia and hypertrophy of VSMC derived from normotensive and hypertensive rats, and in vivo upon intimal thickening induced by carotid artery balloon injury in the rat.