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.
Wolf
Sabine C
SC
Medical Clinic III, Dpartment of Cardiology, Nephrology, Hypertension and Renal Failure, Eberhard-Karls-University, Tübingen, Germany.
Sauter
Gabriele
G
Rodemann
Hans-Peter
HP
Risler
Teut
T
Brehm
Bernhard R
BR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D009392:Nephrectomy; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000235:genetics*; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000077214:Becaplermin; C052035:trandolapril; D019808:Losartan