Treatment of streptozotocin-induced diabetic rats with AVE7688, a vasopeptidase inhibitor - Effect on vascular and neural disease
Treatment of streptozotocin-induced diabetic rats with AVE7688, a vasopeptidase inhibitor - Effect on vascular and neural disease
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DOI：
10.2337/db06-1180
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发表时间：
2007-02-01
期刊：
影响因子：
7.7
通讯作者：
Yorek, Mark A.
中科院分区：
文献类型：
--
作者：
Davidson, Eric P.;Kleinschmidt, Travis L.;Yorek, Mark A.
在神经外动脉中，乙酰胆碱介导的血管舒张是由一氧化氮和内皮源性超极化因子（EDHF）介导的，这两种机制都受到糖尿病的损害。EDHF作用的介质是未知的。在神经外小动脉中，c型利钠肽（CNP）具有与edhf样活性一致的特性。神经外小动脉表达CNP，外源性CNP引起浓度依赖性血管松弛。在链脲佐菌素诱导的糖尿病大鼠中，cnp介导的神经外小动脉血管松弛减少。由于CNP可能是血管功能的调节剂，血管肽酶抑制剂可能是糖尿病诱导的血管和神经疾病的有效治疗方法。血管肽酶抑制剂抑制ACE活性和中性内肽酶，其降解利钠肽。在糖尿病未治疗4周后，用血管肽酶抑制剂AVE7688 （450 mg/kg）治疗链脲佐菌素诱导的糖尿病大鼠8-10周。糖尿病大鼠的治疗纠正了糖尿病引起的神经内血流减少，显著改善了运动和感觉神经传导速度，阻止了后爪痛觉减退的发展，降低了神经外小动脉中的超氧化物和硝基酪氨酸水平。糖尿病引起的乙酰胆碱介导的神经外小动脉血管舒张的减少随着治疗而明显改善。这些研究提示血管肽酶抑制剂可能是治疗糖尿病血管和神经功能障碍的有效途径。
In epineurial arterioles, acetylcholine-mediated vascular relaxation is mediated by nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), and both mechanisms are impaired by diabetes. The mediator responsible for the effect of EDHF is unknown. In epineurial arterioles, C-type natriuretic peptide (CNP) has properties consistent with EDHF-like activity. Epineurial arterioles express CNP, and exogenous CNP causes a concentration-dependent vascular relaxation. In streptozotocin-induced diabetic rats, CNP-mediated vascular relaxation in epineurial arterioles is decreased. Since CNP may be a regulator of vascular function, a vasopeptidase inhibitor may be an effective treatment for diabetes-induced vascular and neural disease. Vasopeptidase inhibitors inhibit ACE activity and neutral endopeptidase, which degrades natriuretic peptides. Streptozotocin-induced diabetic rats were treated with AVE7688 (450 mg/kg in the diet), a vasopeptidase inhibitor, for 8-10 weeks after 4 weeks of untreated diabetes. Treatment of diabetic rats corrected the diabetes-induced decrease in endoneurial blood flow, significantly improved motor and sensory nerve conduction velocity, prevented the development of hypoalgesia in the hind paw, and reduced superoxide and nitrotyrosine levels in epineurial arterioles. The diabetes-induced decrease in acetylcholine-mediated vascular relaxation by epineurial arterioles was significantly improved with treatment. These studies suggest that vasopeptidase inhibitors may be an effective approach for the treatment of diabetic vascular and neural dysfunction.