Effects of Combined Endothelin and Angiotensin II Antagonism on Growth Factor-Induced Proliferation of Vascular Smooth Muscle Cells Isolated from Uremic Rats

Abstract

Background. The activation of both the renin–angiotensin–aldosterone and endothelin (ET) system in uremia contributes to the development of cardiovascular disease. The combination of ET receptor antagonists and inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II type 1 (AT₁) receptor could therefore inhibit atherogenesis. We studied the effects of different medications on growth-factor-induced proliferation of vascular smooth muscle cells (VSMC) isolated from uremic rats. Methods. Subtotally nephrectomized rats (SNX) were treated with an ET_A receptor antagonist, losartan, trandolapril, or the combinations of an ET_A receptor antagonist and losartan or trandolapril for 12 weeks. Proliferation induced by different growth factors in isolated aortal SMC was measured using a BrdU-ELISA. Results. Maximum proliferation in response to PDGF-BB, bFGF, and TNF-α which was higher in untreated SNX than in controls (PDGF-BB: 486.60 ± 8.27% versus 346.74 ± 4.60%, n = 8), was reduced after monotherapy with losartan or the ET_A receptor antagonist. VSMC from trandolapril-treated rats showed an increased response to all growth factors (PDGF-BB: 663.48 ± 7.00%, n = 8). After combined therapy with the ET_A receptor antagonist and trandolapril, maximum proliferation was lower than in untreated SNX (PDGF-BB: 162.6 ± 1.40%; n = 8; p ≤ 0.01). Combined treatment with losartan and the ET_A receptor antagonist attenuated the maximum levels of VSMC proliferation induced by PDGF-BB, bFGF, and TNF. Conclusions. In contrast to an increased response after trandolapril monotherapy, combined treatment of SNX with an ET_A receptor antagonist and trandolapril reduced growth-factor-induced VSMC proliferation in vitro. Further investigations in uremic patients have to clarify whether the combination of endothelin receptor antagonists and ACE inhibitors inhibits atherogenesis.

• proliferation
• smooth muscle cell
• uremia
• ACE inhibitor
• AT₁ blocker
• endothelin receptor antagonist