BSF-302146

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.

The role of endothelin-1 (ET-1) and of its receptor A (ETA) blockade in oedematous acute pancreatitis (AP) remains unclear. In 40 male Wistar rats with i.p. cerulein-induced AP, lasting 4 hours, ET-1 2x0.5 nmol/kg and 2x1.0 nmol/kg or selective ETA antagonist LU 302146, 10 mg/kg and 20 mg/kg was given i.p. simultaneously with cerulein. Histological and ultrastructural studies of pancreatic specimens were done. ET-1 decreased the inflammatory infiltration, but not the mean scores of necrosis and vacuolization in AP. The ultrastructural damage of acinar cells was less evident after ET-1 than in untreated AP. Selective ETA antagonist slightly aggravated the vacuolization and necrosis of acinar cells and some ultrastructural alterations in AP. In conclusion, ET-1, in contrast to selective ETA antagonist, exerts some protective effect in the early course of oedematous cerulein-induced acute pancreatitis in rats.