title: 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.
abstract: 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 10(-9) M Sar1-All (IC50 = 0.49 x 10(-9) M and 0.79 x 10(-9) M, respectively). Maximum [3H]leucine incorporation was also achieved at 10(-9) M All. 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. All dose-dependently increased FN release, which was also equally inhibited by about 50% with both compounds at 10(-6) M. Furthermore, All 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, All 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.
authors.affiliation: Centre de recherche Roussel-Uclaf, Romainville, France.
authors.forename: F W
authors.initials: FW
authors.lastname: Dunn
authors.forename: M H
authors.initials: MH
authors.lastname: Roux
authors.forename: F
authors.initials: F
authors.lastname: Farhadian
authors.forename: K
authors.initials: K
authors.lastname: Sabri
authors.forename: C
authors.initials: C
authors.lastname: Ossart
authors.forename: J L
authors.initials: JL
authors.lastname: Samuel
authors.forename: L
authors.initials: L
authors.lastname: Rappaport
authors.forename: G
authors.initials: G
authors.lastname: Hamon
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D007930:Leucine / Q000378:metabolism; D019808:Losartan; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D005353:Fibronectins; D007093:Imidazoles; D012333:RNA, Messenger; D013777:Tetrazoles; C094626:fonsartan; D000804:Angiotensin II; C066026:losartan carboxylic acid; D007930:Leucine; D019808:Losartan