Influence of growth factors on the proliferation of vascular smooth muscle cells isolated from subtotally nephrectomized rats after endothelin or angiotensin II antagonism.

Background: Cardiovascular disease is the most important cause of death in patients with end-stage renal disease. In uraemia, the renin-angiotensin-aldosterone and endothelin (ET) systems are activated. It is not known whether inhibition of these systems attenuates the proliferation of isolated smooth muscle cells of uraemic rats.

Methods: Subtotally nephrectomized (SNX) rats were treated with an ET(A) receptor antagonist, an ET(AB) receptor antagonist, the angiotensin type 1 (AT1) receptor antagonist losartan (all 10 mg/kg body weight/day) or the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.1 mg/kg body weight/day) or received no medication (SNX) for 12 weeks. Then, aortal smooth muscle cells (SMCs) were isolated and cultivated. After incubation of SMCs with different growth factors (5-7 days), proliferation was measured using a bromodeoxyuridine enzyme-linked immunosorbent assay (BrdU ELISA).

Results: Higher maximum levels of proliferation were found in SMCs from untreated SNX rats than in SMCs from control animals [platelet-derived growth factor-BB (PDGF-BB) 486.60+/-8.27 vs 346.74+/-4.60%, basic fibroblast growth factor (bFGF) 176.68+/-6.50 vs 123.71+/-1.49%, tumour necrosis factor-alpha (TNF-alpha) 153.38+/-10.16 vs 122.27+/-1.41%]. Treatment with ET receptor antagonists or losartan attenuated growth factor-stimulated proliferation (PDGF-BB: ET(A) receptor antagonist, 135.71+/-1.08%; ET(AB) receptor antagonist, 122.72+/-0.58%; losartan: 103.69+/-1.83%, n = 8). SMCs from trandolapril-treated rats showed an increased response (PDGF-BB 663.48+/-7.00%, n = 8).

Conclusions: Treatment of SNX rats with ET receptor antagonists or losartan reduced growth factor-induced SMC proliferation in vitro. However, further investigations with uraemic patients have to clarify whether angiotensin or ET receptor antagonists inhibit the development of atherosclerosis.