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 role in vascular occlusive disorders such as atherosclerosis and restenosis following balloon angioplasty. Among the factors that may be important in the development of vascular lesions, several authors have reported that the local angiotensin system participates in modulating the proliferation 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 compound is a potent and competitive antagonist of the binding of [I-125]angiotensin II to its receptor on cultured human aortic smooth muscle cells, 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). Angiotensin II is a potent mitogen for human aortic smooth muscle cells in culture, exhibiting a maximum proliferative response at 1 mu M SR 47436 and Losartan prevented angiotensin II-induced proliferation of these 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 inhibition of serum-induced smooth muscle cell proliferation (IC50 = 5.5 + 0.8 mu M). A selective AT(2) receptor antagonist, PD 123177 did not affect angiotensin II-induced responses in these cells. This in vitro study 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 associated with the development of atherosclerosis, restenosis and hypertension.