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 AT(1) receptor antagonist, for vascul ar AT(1) receptors from normotensive and hypertensive rats and to inve stigate in vitro, its effects on angiotensin II (AII)-induced hyperpla sia and hypertrophy of vascular smooth muscle cells (VSMC). In additio n the in vivo effects of UP 269-6 on neointimal proliferation in a car otid artery balloon injury in normotensive rats were also investigated . 2 UP 269-6 selectively inhibited [I-125]-Sar(1)-IIe(8)-AII binding t o vascular AT(1) receptors present on VSMC derived from normotensive W istar rat and from SHR (K-i = 16.6 +/- 3.6 nM and 7.5 +/- 2.0 nM, resp ectively). In comparison, losartan and its metabolite, EXP 3174, inhib ited [I-125]-Sar(1)-Ile(8)-AII binding to vascular AT(1) receptors der ived from both cell models with K-i values slightly lower (losartan) a nd higher (EXP 3174), respectively, than that of UP 269-6. 3 AII (1 mu M) induced a weak and variable hyperplastic response (4 to 32% increa se in cell number) in Wistar rat VSMC after 96 h. 4 AII (1 mu M) induc ed 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 n early the same inhibitory potency, compared to UP 269-6. UP 269-6 (1 m u M) inhibited nearly completely the action of AII. 5 AII (500 nM) cau sed maximal stimulation of protein synthesis in Wistar rat VSMC (117+/ -36%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulat ion with IC50 values of 28 +/- 6 nM, 3504 +/- 892 nM and 21 +/- 3 nM, respectively. 6 AII (50 nM) induced maximal stimulation of protein syn thesis in SHR VSMC (237 +/- 67%). UP 269-6, losartan and EXP 3174 tota lly 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) da y(-1)) administered orally in the diet for 20 days induced a 38% reduc tion in neointimal area and a 36% reduction in neointima/media ratio a ssociated with the intimal thickening induced by carotid artery balloo n injury. 8 In conclusion, UP 269-6 was shown to be a potent antiproli ferative agent both in vitro on AII-induced hyperplasia and hypertroph y of VSMC derived from normotensive and hypertensive rats. and in vitr o upon intimal thickening induced by carotid artery balloon injury in the rat.