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 I (ATI) receptor antagonists remarkably reduced intimal lesions in rats following balloon injury. Using vascular smooth muscle cells (VSMC) in culture, we tested the hypothesis that other classical growth factors may enhance AII effects on VSMC growth, and ATI receptor antagonists may inhibit these effects. AII, platelet-derived growth factor-BB (PDGF-BB), and epidermal growth factor (EGF) caused a 3426 +/- 262%, 277 +/- 69%, and 1568 +/- 62% increase in [3H]thymidine incorporation in VSMC (mean +/- SD, n = 3), respectively. The exposure of the cells to AII in combination with PDGF-BB or EGF resulted in an approximately 2-fold or 1.5-fold elevation of the AII-dependent effect, respectively. 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7- carboxylic acid (CV-11974), the active metabolite of the specific nonpeptide AT1 receptor antagonist (+/-)-1-cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole- 7-carboxylate (TCV-116, Candesartan), suppressed the effect of AII down to basal values, as well as reducing the synergistic effect of PDGF or the additive effect of EGF on AII-induced [3H]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 blocked the effect of AII, as well as the additive effect of PDGF-BB on cell number. From these findings, it may be concluded that AT1 receptor antagonists may reduce or prevent the development of intimal lesions following vascular injury through inhibition of direct and indirect growth-promoting effects of AII in VSMC.