CV-11974, THE ACTIVE METABOLITE OF TCV-116 (CANDESARTEN), INHIBITS THE SYNERGISTIC OR ADDITIVE EFFECT OF DIFFERENT GROWTH-FACTORS ON ANGIOTENSIN-II-INDUCED PROLIFERATION OF VASCULAR SMOOTH-MUSCLE CELLS

Many previous studies have demonstrated that angiotensin II (AII) type 1 (AT1) receptor antagonists remarkably reduced intimal lesions in ra ts following balloon injury. Using vascular smooth muscle cells (VSMC) in culture, we tested the hypothesis that other classical growth fact ors may enhance AII effects on VSMC growth, and AT1 receptor antagonis ts may inhibit these effects. AII, platelet-derived growth factor-BB ( PDGF BB), and epidermal growth factor (EGF) caused a 3426 +/- 262%, 27 7 +/- 69%, and 1568 +/- 62% increase in [H-3]thymidine incorporation i n VSMC (mean +/- SD, n = 3), respectively. The exposure of the cells t o AIIin combination with PDGF-BB or EGF resulted in an approximately 2 -fold or 1.5-fold elevation of the AII dependent effect, respectively. iphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV-11974), t he active metabolite of the specific nonpeptide AT(1) receptor antagon ist (+/-) 1-cyclohexyloxycarbonyloxy)ethyl phenyl-4-yl]methyl]-1H-benz imidazole-7-carboxylate (TCV-116, Candesartan), suppressed the effect of AII down to basal values, as well as reducing the synergistic effec t of PDGF or the additive effect of EGF on AII-induced [H-3]thymidine incorporation. AII and PDGF-BB per se induced 57 +/- 19 and 70 +/- 14% increase in VSMC number. Combination of both agonists resulted in a 2 -fold increase of the AII effect on cell number. Again, CV-11974 block ed the effect of AII, as well as the additive effect of PDGF-BB on cel l number. From these findings, it may be concluded that AT1 receptor a ntagonists may reduce or prevent the development of intimal lesions fo llowing vascular injury through inhibition of direct and indirect grow th promoting effects of AII in VSMC.