EFFECT OF SR-47436, A NOVEL ANGIOTENSIN-II AT(1) RECEPTOR ANTAGONIST,ON HUMAN VASCULAR SMOOTH-MUSCLE CELLS IN-VITRO

Proliferation of smooth muscle cells within the intima plays a key rol e in vascular occlusive disorders such as atherosclerosis and restenos is following balloon angioplasty. Among the factors that may be import ant in the development of vascular lesions, several authors have repor ted that the local angiotensin system participates in modulating the p roliferation of smooth muscle cells after arterial injury. This study was therefore designed to characterize the antagonistic properties and to investigate the antiproliferative effect of a newly developed non- peptide angiotensin II AT(1) receptor antagonist, SR 47436. This compo und is a potent and competitive antagonist of the binding of [I-125]an giotensin II to its receptor on cultured human aortic smooth muscle ce lls, exhibiting an IC50 value of 1.7 +/- 0.6 nM. SR 47436 was 10-fold more potent than DuP 753 (Losartan) (IC50 = 20.8 +/- 3.7 nM). In these same cells, SR 1.7 +/- 0.6 nM. SR 47436 was 10-fold more potent than DuP 753 (Losartan)(IC50 = 20.8 +/- 3.7 7.4 +/- 1.3 nM for DuP 753). An giotensin II is a potent mitogen for human aortic smooth muscle cells in culture, exhibiting a maximum proliferative response at 1 mu M SR 4 7436 and Losartan prevented angiotensin II-induced proliferation of th ese cells in a dose-dependent manner (IC50 = 0.32 +/- 0.09 and 0.71 +/ - 0.8 mu M, respectively). SR 47436 displayed a marked in vitro inhibi tion of serum-induced smooth muscle cell proliferation (IC50 = 5.5 + 0 .8 mu M). A selective AT(2) receptor antagonist, PD 123177 did not aff ect angiotensin II-induced responses in these cells. This in vitro stu dy shows that SR 47436 is a potent inhibitor of angiotensin II-induced smooth muscle cell growth and thus may have beneficial effects in the development and regression of vascular hypertrophy, which is associat ed with the development of atherosclerosis, restenosis and hypertensio n.