Effects of moexiprilat on oestrogen-stimulated cardiac fibroblast growth.

1. The effects of 2-2-(1-(ethoxycarbonyl)-3-phenylpropyl)-[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (moexiprilat), 17beta-oestradiol (E2), oestrone (ES) and angiotensin II (AII) on growth and activation of oestrogen receptors and the immediate-early gene egr-1 were investigated in neonatal rat cardiac fibroblasts of female and male origin. 2. In BrdU proliferation assays, oestrone (10(-7)- 10(-9) M) stimulated cardiac fibroblast growth in a concentration-dependent fashion (maximum at 10(-7) M, 4.0 fold +/- 0.14 in female and 3.1 fold +/- 0.06 in male cells, n=9, P<0.05), while E2 (10(-7)-10(-9) M) had no effect. Moexiprilat (10(-7)M) completely inhibited oestrone-induced cardiac fibroblast growth. 3. Angiotensin 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 (maximum 47.5 fold at 60 min) expression in a time-dependent fashion. 4. In immunoblot experiments, oestrogen activated oestrogen receptor (ES: 12.8 fold +/- 2.0; E2: 14.7 fold +/- 4.9; n=3, P<0.05) and egr-1 (ES: 5.1 fold, +/- 0.24; E2: 3.8 fold, +/- 0.25; n=3, P<0.05) expression. The induction of oestrogen receptor and egr-1 protein expression was time-dependent and inhibited by moexiprilat. 5. Our results show that oestrone and 17beta-oestradiol reveal a significant difference in their potential to activate cardiac fibroblast growth in female and male cells and that oestrone-stimulated growth is inhibited by moexiprilat. The inhibition of oestrone-stimulated cardiac fibroblast growth by moexiprilat may contribute to the beneficial effects seen in postmenopausal women with hypertensive heart disease treated with ACE inhibitors.