OBJECTIVE: To study the features of vascular smooth muscle cell (VSMC) proliferation induced by endothelin-1 (ET-1). METHODS: VSMCs of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were cultured and trea...OBJECTIVE: To study the features of vascular smooth muscle cell (VSMC) proliferation induced by endothelin-1 (ET-1). METHODS: VSMCs of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were cultured and treated with ET-1. Basic fibroblast growth factor (bFGF) gene expression was measured using both Northern blot and an enzyme-linked immunoassay. RESULTS: ET-1 resulted in an increase in bFGF transcripts at 8 - 24 h; bFGF levels were significantly higher in VSMCs treated with ET-1 than in those not treated. However, VSMCs growth responses in SHR and WKY were different. Smooth muscle cells of SHR were hyper-responsive to ET-1. Maximal bFGF mRNA levels were elevated 3.5-fold at 4 h of stimulation in WKY and 8-fold at 8h in SHR4. Moreover, the proliferation of VSMCs induced by ET-1 was inhibited by antisense phosphorothioate oligodeoxynucleotides (10 micromol/L AS-bFGF) but not sense bFGF oligomers at the same concentrations, being reduced by 80% in SHR and 40% in WKY vs control, respectively. Furthermore, the effect of AS-bFGF oligomers on SHR SMC proliferation is significantly greater than on WKY SMC proliferation. CONCLUSION: ET-1 may be required for exaggerated vascular growth responses in SHR and bFGF may be involved.展开更多
OBJECTIVE: To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, ...OBJECTIVE: To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes. METHODS: Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week. RESULTS: Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters. CONCLUSION: Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.展开更多
文摘OBJECTIVE: To study the features of vascular smooth muscle cell (VSMC) proliferation induced by endothelin-1 (ET-1). METHODS: VSMCs of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were cultured and treated with ET-1. Basic fibroblast growth factor (bFGF) gene expression was measured using both Northern blot and an enzyme-linked immunoassay. RESULTS: ET-1 resulted in an increase in bFGF transcripts at 8 - 24 h; bFGF levels were significantly higher in VSMCs treated with ET-1 than in those not treated. However, VSMCs growth responses in SHR and WKY were different. Smooth muscle cells of SHR were hyper-responsive to ET-1. Maximal bFGF mRNA levels were elevated 3.5-fold at 4 h of stimulation in WKY and 8-fold at 8h in SHR4. Moreover, the proliferation of VSMCs induced by ET-1 was inhibited by antisense phosphorothioate oligodeoxynucleotides (10 micromol/L AS-bFGF) but not sense bFGF oligomers at the same concentrations, being reduced by 80% in SHR and 40% in WKY vs control, respectively. Furthermore, the effect of AS-bFGF oligomers on SHR SMC proliferation is significantly greater than on WKY SMC proliferation. CONCLUSION: ET-1 may be required for exaggerated vascular growth responses in SHR and bFGF may be involved.
基金ThisresearchworkwassupportedbyMinistryofPublicHealthandShanghaiBairenProjectFoundation (No .98BR0 3 8)
文摘OBJECTIVE: To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes. METHODS: Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week. RESULTS: Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters. CONCLUSION: Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.
