EFFECTS OF MOEXIPRILAT ON ESTROGEN-STIMULATED CARDIAC FIBROBLAST GROWTH

1 The effects of yl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3 ca rboxylic acid (moexiprilat), 17 beta-oestradiol (E-2), oestrone (ES) a nd angiotensin II (AII) on growth and activation of oestrogen receptor s and the immediate-early gene egr-1 were investigated in neonatal rat cardiac fibroblasts of female and male origin. 2 In BrdU proliferatio n assays, oestrone (10(-7)-10(-9) M) stimulated cardiac fibroblast gro wth in a concentration-dependent fashion (maximum at 10(-7) M, 4.0 fol d +/- 0.14 in female and 3.1 fold +/- 0.06 in male cells, n = 9, P < 0 .05), while E-2 (10(-7)-10(-9) M) had no effect. Moexiprilat (10(-7) M ) completely inhibited oestrone-induced cardiac fibroblast growth. 3 A ngiotensin II (10(-7) M) induced cardiac fibroblast growth (female 4.1 fold +/- 0.1/male 3.9 fold +/- 0.2; n = 9, P < 0.05). Angiotensin II induced oestrogen receptor (maximum 21.8 fold at 60 min) and egr-1 (ma ximum 47.5 fold at 60 min) expression in a time-dependent fashion. 4 I n immunoblot experiments, oestrogen activated oestrogen receptor (ES: 12.8 fold +/- 2.0; E-2: 14.7 fold +/- 4.9; n = 3, P < 0.05) and egr-1 (ES: 5.1 fold, +/- 0.24; E-2: 3.8 fold, +/- 0.25; n = 3, P < 0.05) exp ression. The induction of oestrogen receptor and egr-1 protein express ion was time-dependent and inhibited by moexiprilat. 5 Our results sho w that oestrone and 17 beta-oestradiol reveal a significant difference in their potential to activate cardiac fibroblast growth in female an d male cells and that oestrone-stimulated growth is inhibited by moexi prilat. The inhibition of oestrone-stimulated cardiac fibroblast growt h by moexiprilat may contribute to the beneficial effects seen in post menopausal women with hypertensive heart disease treated with ACE inhi bitors.