Wolf Sabine C, Sauter Gabriele, Risler Teut, Brehm Bernhard R
Medical Clinic IV, Department of Hypertension and Renal Failure and Endocrinology, University of Tübingen, Tübingen, Germany.
Ren Fail. 2005;27(4):465-74.
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 (AT,) 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.
Subtotally nephrectomized rats (SNX) were treated with an ETA receptor antagonist, losartan, trandolapril, or the combinations of an ETA 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.
Maximum proliferation in response to PDGF-BB, bFGF, and TNF-alpha 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 ETA 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 ETA receptor antagonist and trandolapril, maximum proliferation was lower than in untreated SNX (PDGF-BB: 162.6 +/- 1.40%; n=8; p < or = 0.01). Combined treatment with losartan and the ETA receptor antagonist attenuated the maximum levels of VSMC proliferation induced by PDGF-BB, bFGF, and TNF.
In contrast to an increased response after trandolapril monotherapy, combined treatment of SNX with an ETA 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.
肾素 - 血管紧张素 - 醛固酮系统和内皮素（ET）系统在尿毒症中的激活均有助于心血管疾病的发展。因此，ET受体拮抗剂与血管紧张素转换酶（ACE）抑制剂或血管紧张素II 1型（AT₁）受体拮抗剂联合使用可能会抑制动脉粥样硬化的发生。我们研究了不同药物对从尿毒症大鼠分离的血管平滑肌细胞（VSMC）生长因子诱导增殖的影响。
对次全肾切除大鼠（SNX）用ET₁受体拮抗剂、氯沙坦、trandolapril或ET₁受体拮抗剂与氯沙坦或trandolapril的组合进行治疗，为期12周。使用BrdU - ELISA测量分离的主动脉平滑肌细胞中不同生长因子诱导的增殖。
未治疗的SNX对血小板衍生生长因子 - BB（PDGF - BB）、碱性成纤维细胞生长因子（bFGF）和肿瘤坏死因子 - α（TNF - α）的最大增殖反应高于对照组（PDGF - BB：486.60±8.27%对346.74±4.60%，n = 8），氯沙坦或ET₁受体拮抗剂单药治疗后降低。trandolapril治疗的大鼠的VSMC对所有生长因子的反应增加（PDGF - BB：663.48±7.00%，n = 8）。ET₁受体拮抗剂与trandolapril联合治疗后，最大增殖低于未治疗的SNX（PDGF - BB：162.6±1.40%；n = 8；p≤0.01）。氯沙坦与ET₁受体拮抗剂联合治疗减弱了PDGF - BB、bFGF和TNF诱导的VSMC增殖的最大水平。
与trandolapril单药治疗后反应增加相反，ET₁受体拮抗剂与trandolapril联合治疗SNX可降低体外生长因子诱导的VSMC增殖。对尿毒症患者的进一步研究必须阐明内皮素受体拮抗剂与ACE抑制剂联合使用是否能抑制动脉粥样硬化的发生。
