Arginase inhibition alleviates hypertension associated with diabetes: Effect on endothelial dependent relaxation and NO production
Arginase inhibition alleviates hypertension associated with diabetes: Effect on endothelial dependent relaxation and NO production
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DOI：
10.1016/j.vph.2012.01.001
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发表时间：
2012-11-01
影响因子：
4
通讯作者：
Fahmy, Ahmed
中科院分区：
文献类型：
--
作者：
El-Bassossy, Hany M.;El-Fawal, Rania;Fahmy, Ahmed
精氨酸酶活性升高在以血管功能障碍为特征的各种疾病中已有报道。在本研究中，研究了精氨酸酶抑制对糖尿病相关高血压的潜在保护作用。糖尿病是由链脲佐菌素诱导的，而精氨酸酶抑制剂；瓜氨酸，去甲伐他林和鸟氨酸，在过去的6周里每天都被给予。检测血压、血糖、糖基化终产物(AGEs)和精氨酸酶活性。获得了苯肾上腺素(PE)、氯化钾和乙酰胆碱(ACh)在胸主动脉环上的浓度反应曲线。糖尿病动物的精氨酸酶活性明显升高，而瓜氨酸、去甲缬氨酸或鸟氨酸显著抑制精氨酸酶活性。糖尿病与收缩压和舒张压升高有关，而抑制精氨酸酶显著降低舒张压升高。糖尿病使血管对PE和KCl的收缩反应增强，对ACh的松弛反应减弱，而精氨酸酶的抑制完全阻止了对ACh的反应减弱。糖尿病减少ACh刺激的NO，但增加ROS的产生，而抑制精氨酸酶则恢复正常的NO和ROS的产生。此外，与精氨酸酶抑制剂的急性孵育改善了糖尿病动物分离的主动脉对ACh的反应，但不能改善PE或KCl。糖尿病与血清AGEs显著增加有关，而所有使用的精氨酸酶抑制剂均使其正常化。精氨酸酶抑制通过抑制内皮依赖性松弛和NO的产生来减轻糖尿病患者的高血压。(C)2012 Elsevier Inc.保留所有权利。
Increased arginase activity has been reported in a variety of disease conditions characterized by vascular dysfunction. In the present study, the potentially protective effect of arginase inhibition against the hypertension associated with diabetes has been investigated.Diabetes was induced by streptozotocin while arginase inhibitors; citrulline, norvaline and ornithine, were daily administered in the last 6 weeks. At the end of study, blood pressure (BP), serum levels of glucose, advanced glycation end products (AGEs) and arginase activity were determined. Concentration response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) were obtained in thoracic aorta rings. ACh-induced NO and reactive oxygen species (ROS) generation in aorta were also studied.Arginase activity was elevated in diabetic animals while significantly inhibited by citrulline, norvaline or ornithine. Diabetes was associated with elevation in systolic and diastolic BP while, arginase inhibition significantly reduced the elevation in diastolic BP. Diabetes increased contractile response of aorta to PE and KCl, decreased relaxation response to ACh while arginase inhibition completely prevented the impaired response to ACh. Diabetes reduces ACh stimulated NO but increased ROS generation while arginase inhibition restores normal NO and ROS generation. In addition, acute incubation with arginase inhibitors improved response to ACh but not PE or KCl in aorta isolated from diabetic animals. Diabetes was associated with a significant increase in serum AGEs while all the used arginase inhibitors normalize it.In conclusion. arginase inhibition alleviates hypertension in diabetes through a mechanism involving prevention of the impairment in endothelial dependent relaxation and NO production. (C) 2012 Elsevier Inc. All rights reserved.