HR-720, A NOVEL ANGIOTENSIN RECEPTOR ANTAGONIST INHIBITS THE ANGIOTENSIN-II-INDUCED TROPHIC EFFECTS, FIBRONECTIN RELEASE AND FIBRONECTIN-EIIIA(-MUSCLE CELLS IN-VITRO() EXPRESSION IN RAT AORTIC VASCULAR SMOOTH)

The aim of this study was to evaluate the direct trophic effects of an giotensin 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 anta gonist with some AT2 receptor affinity, were compared with those of se lective AT1 antagonist EXP 3174. Both HR 720 and EXP 3174 inhibited in a concentration-dependent manner the maximum increase in cell volume induced by 10(-9) M Sar(1)-AII (IC50 = 0.49 x 10(-9) M and 0.79 x 10(- 9) M, respectively). Maximum [H-3]leucine incorporation was also achie ved at 10(-9) M AII. HR 720 blocked the increase in protein synthesis with potency similar to EXP 3174; the respective IC50 values were 1.04 x 10(-9) M and 1.36 x 10(-9) M. AII dose-dependently increased FN rel ease, which was also equally inhibited by about 50% with both compound s at 10(-8) M. Furthermore, AII enhanced FN-EIIIA(+) mRNA in rat vascu lar smooth muscle cells (VSMC), which indicated a modulation of FN iso form 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 ex pression 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.