In:
British Journal of Pharmacology, Wiley, Vol. 120, No. 3 ( 1997-01), p. 488-494
Abstract:
The present studies were designed to measure the affinity of UP 269‐6, a newly developed angiotensin AT 1 receptor antagonist, for vascular AT 1 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. UP 269‐6 selectively inhibited [ 125 I]‐Sar 1 ‐Ile 8 ‐AII binding to vascular AT 1 receptors present on VSMC derived from normotensive Wistar rat and from SHR (K i = 16.6 ± 3.6 nM and 7.5 ± 2.0 nM, respectively). In comparison, losartan and its metabolite, EXP 3174, inhibited [ 125 I‐Sar 1 ‐Ile 8 ‐AII binding to vascular AT 1 receptors derived from both cell models with K i values slightly lower (losartan) and higher (EXP 3174), respectively, than that of UP 269‐6. AII (1 μM) induced a weak and variable hyperplastic response (4 to 32% increase in cell number) in Wistar rat VSMC after 96 h. 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 IC 50 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. 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 IC 50 values of 28 ± 6 nM, 3504 ± 892 nM and 21±3 nM, respectively. 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 IC 50 values of 16 ± 3 nM, 282± 122 nM and 3.3 ± 1.0 nM, respectively. 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. 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.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1038/sj.bjp.0700897
Language:
English
Publisher:
Wiley
Publication Date:
1997
detail.hit.zdb_id:
80081-8
detail.hit.zdb_id:
2029728-2
SSG:
15,3
Permalink