Effects of combined endothelin and angiotensin II antagonism on growth factor-induced proliferation of vascular smooth muscle cells isolated from uremic rats.
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 (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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wolf
Sabine C
SC
Medical Clinic IV, Department of Hypertension and Renal Failure and Endocrinology, University of Tübingen, Tübingen, Germany.
Sauter
Gabriele
G
Risler
Teut
T
Brehm
Bernhard R
BR
D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007211:Indoles / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D009392:Nephrectomy; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D012680:Sensitivity and Specificity; D014511:Uremia / Q000188:drug therapy* / Q000473:pathology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril; D019808:Losartan