Influence of endothelin receptor antagonism on smooth muscle cell proliferation after chronic renal failure

Uremic patients suffer from an accelerated development of atherosclerosis. In uremia the angiotensin-aldosterone-endothelin system is activated. It is not known, however, whether endothelin receptor antagonism inhibits atherosclerosis in uremia. An experimental model of mild renal insufficiency is subtotal nephrectomy in rats. The aim of this study was to assess the proliferative response of vascular smooth muscle cells from rats that have undergone subtotal nephrectomy and are treated with an endothelin-A or combined endothelin-A/endothelin-B receptor antagonist to the proatherogenic growth factors platelet-derived growth factor-BB and basic fibroblast growth factor. For 12 weeks 5/6-nephrectomized rats were treated with the endothelin-A receptor antagonist LU 302146 or the combined endothelin-A/endothelin-B receptor antagonist LU 302872 (10 mg/kg bodyweight)or received no medication (subtotal nephrectomy). Aortal smooth muscle cells were isolated and cultivated. After incubation with platelet-derived growth factor-BB (10(-13)-10(-9) mol/L for 5 days) or basic fibroblast growth factor (10(-14)-10(-10) mol/L for 7 days) proliferation was measured using bromodeoxyuridine enzyme-linked immunosorbent assay. Both growth factors increased proliferation in vascular smooth muscle cells from untreated subtotally nephrectomized rats (platelet-derived growth factor-BB10(-9) mol/L: 487%, basic fibroblast growth factor 10(-10) mol/L:175%). Treatment with the endothelin-A receptor antagonist resulted in a reduced proliferation (platelet-derived growth factor-BB: 137%, basic fibroblast growth factor: 109%). After treatment with the combined endothelin-A/endothelin-B receptor antagonist findings were similar (platelet-derived growth factor-BB: 123%,basic fibroblast growth factor: 110%). These data demonstrate that chronic endothelin-A and combined endothelin-A/endothelin-B receptor antagonism inhibits vascular smooth muscle cell proliferation in rats treated with subtotal nephrectomy. This indicates a regulatory influence of these drugs on gene transcription and supports the importance of early treatment to inhibit coronary artery disease in uremic patients.