Vol. 280, Issue 1, 447-453, 1997

HR 720, A Novel Angiotensin Receptor Antagonist Inhibits the Angiotensin II-Induced Trophic Effects, Fibronectin Release and Fibronectin-EIIIA⁺ Expression in Rat Aortic Vascular Smooth Muscle Cells in Vitro

F. W. Dunn, M.-H. Roux, F. Farhadian, K. Sabri, C. Ossart, J. L. Samuel, L. Rappaport and G. Hamon

Centre de recherche Roussel-Uclaf (F.W.D., M-H.R., C.O., G.H.), 93235 Romainville Cedex, France and Institut National de la Santé et de la Recherche Médicale U 127 (F.F., K.S., J.L.S., L.R.), 75010 Paris, France

The aim of this study was to evaluate the direct trophic effects of angiotensin II (AII) on rat vascular smooth muscle cells obtained from a single cellular isolate. Cell volume, protein synthesis, fibronectin (FN) release and FN-EIIIA⁺ mRNA isoform expression were analyzed in parallel. The effects of HR 720, a novel AT1 angiotensin receptor antagonist with some AT2 receptor affinity, were compared with those of selective AT1 antagonist EXP 3174. Both HR 720 and EXP 3174 inhibited in a concentration-dependent manner the maximum increase in cell volume induced by 10⁹ M Sar¹-AII (IC₅₀ = 0.49 × 10⁹ M and 0.79 × 10⁹ M, respectively). Maximum [³H]leucine incorporation was also achieved at 10⁹ M AII. HR 720 blocked the increase in protein synthesis with potency similar to EXP 3174; the respective IC₅₀ values were 1.04 × 10⁹ M and 1.36 × 10⁹ M. AII dose-dependently increased FN release, which was also equally inhibited by about 50% with both compounds at 10⁸ M. Furthermore, AII enhanced FN-EIIIA⁺ mRNA in rat vascular smooth muscle cells (VSMC), which indicated a modulation of FN isoform expression which was inhibited by angiotensin II antagonists. In conclusion, AII induced parallel and concentration-dependent increases in cell volume, protein synthesis, FN release and FN-EIIIA⁺ mRNA expression in vascular smooth muscle cells. These effects appeared to be essentially mediated by AT1 receptor stimulation as indicated by the equal inhibitory effects of HR 720 and EXP 3174.