Improvement of vascular function by acute and chronic treatment with the PDE‐5 inhibitor sildenafil in experimental diabetes mellitus
Improvement of vascular function by acute and chronic treatment with the PDE‐5 inhibitor sildenafil in experimental diabetes mellitus
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DOI：
10.1038/sj.bjp.0707459
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发表时间：
2008-03
影响因子：
7.3
通讯作者：
A. Schäfer;D. Fraccarollo;Stephanie Pförtsch;U. Flierl;C. Vogt;J. Pfrang;A. Kobsar;Thomas Renné;M. Eigenthaler;Georg Ertl;J. Bauersachs
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文献类型：
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作者：
A. Schäfer;D. Fraccarollo;Stephanie Pförtsch;U. Flierl;C. Vogt;J. Pfrang;A. Kobsar;Thomas Renné;M. Eigenthaler;Georg Ertl;J. Bauersachs
背景和目的糖尿病相关的血管功能障碍会增加心血管风险。我们研究了磷酸二酯酶-5抑制剂西地那非是否会改善糖尿病大鼠的血管功能。实验方法雄性Wistar大鼠用链脲佐菌素（50 mg kg-1，i. v.）诱发胰岛素缺乏型糖尿病在体外研究了西地那非的直接作用以及对内皮依赖性和非依赖性血管舒张的改变。还在糖尿病诱导4周后，在器官浴室中的离体主动脉段中表征了西地那非体内急性和慢性（2周）治疗对血管功能的影响。关键结果西地那非诱导了浓度依赖性血管舒张，一氧化氮（NO）合成酶抑制剂NG-硝基-L-精氨酸可减弱这种作用。乙酰胆碱诱导的内皮依赖性舒张以及NO供体DEA-NONOate诱导的内皮非依赖性舒张在糖尿病大鼠的动脉中显著降低。用西地那非林玻璃体孵育使糖尿病大鼠的血管内皮依赖性和非依赖性舒张正常化。西地那非的急性和慢性体内治疗导致内皮依赖性和非依赖性血管舒张增强。超氧化物的形成增加糖尿病，与增强膜表达的NAD（P）H氧化酶亚基gp 91 phox和Rac，这两个都减少了慢性治疗与sildenafil.Conclusions和implicationsWe表明，西地那非治疗迅速和慢性改善糖尿病大鼠血管舒张。用西地那非治疗可能在糖尿病患者中提供类似的有益效果.British Journal of Pharmacology（2008）153，886-893; doi：10.1038/sj.bjp.0707459; 2007年9月24日在线发表
Background and purposeDiabetes‐associated vascular dysfunction contributes to increased cardiovascular risk. We investigated whether the phosphodiesterase‐5 inhibitor sildenafil would improve vascular function in diabetic rats.Experimental approachMale Wistar rats were injected with streptozotocin (50 mg kg‐1, i.v.) to induce insulin‐deficient diabetes. Direct effects of sildenafil as well as modification of endothelium‐dependent and ‐independent vasorelaxation were investigatedin vitro. The effects of acute and chronic (2 week) treatmentin vivoof sildenafil on vascular function were also characterized in isolated aortic segments in organ bath chambers 4 weeks after diabetes induction.Key resultsSildenafil induced a concentration‐dependent vasorelaxation, which was attenuated by the nitric oxide (NO) synthase inhibitor, NG‐nitro‐L‐arginine. Acetylcholine‐induced endothelium‐dependent as well as endothelium‐independent relaxation induced by the NO donor, DEA‐NONOate, was significantly reduced in aortae from diabetic rats. Incubation with sildenafilin vitronormalized both endothelium‐dependent and ‐independent relaxation in aortae from diabetic rats. Acute as well as chronicin vivotreatment with sildenafil resulted in enhanced endothelium‐dependent and ‐independent vasorelaxation. Superoxide formation was increased in diabetes, associated with enhanced membrane expression of the NAD(P)H oxidase subunit gp91phoxand Rac, which were both reduced by chronic treatment with sildenafil.Conclusions and implicationsWe demonstrate that sildenafil treatment rapidly and chronically improves vascular relaxation in diabetic rats. Treatment with sildenafil might provide a similarly beneficial effect in diabetic patients.British Journal of Pharmacology(2008)153, 886–893; doi:10.1038/sj.bjp.0707459; published online 24 September 2007