Matsumoto Takayuki, Noguchi Eri, Ishida Keiko, Nakayama Naoaki, Kobayashi Tsuneo, Kamata Katsuo
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Eur J Pharmacol. 2008 Dec 3;599(1-3):102-9. doi: 10.1016/j.ejphar.2008.10.006. Epub 2008 Oct 10.
Diabetes mellitus impairs endothelial function, an effect that can be considered a hallmark of the development of cardiovascular diseases in diabetics. Cilostazol, a selective phosphodiesterase 3 inhibitor, is currently used to treat patients with diabetic vascular complications. However, the effects of cilostazol on responses mediated by endothelium-derived relaxing [in particular, nitric oxide (NO) and hyperpolarizing factors (EDHF)] and contracting factors remain unclear. Here, we hypothesized that cilostazol could improve endothelial dysfunctions in mesenteric arteries isolated from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Using cilostazol-treated (100 mg/kg/day for 4 weeks) or -untreated OLETF and control (Long Evans Tokushima Otsuka) rats, we examined the acetylcholine-induced endothelium-dependent responses and the cell-permeant cyclic adenosine monophosphate (cAMP) analog-induced relaxations in the superior mesenteric artery. We also determined blood parameters in these animals. In OLETF rats, chronic treatment with cilostazol reduced the blood levels of triglyceride, non-esterified fatty acids, and leptin, and increased antioxidant capacity, but did not alter the blood glucose or insulin levels. In studies on mesenteric arteries from cilostazol-treated OLETF animals, the cilostazol treatment improved: (a) the acetylcholine-induced EDHF-mediated relaxation and (b) the cAMP-mediated relaxation. However, cilostazol did not alter the NO-mediated relaxation or the endothelium-derived contracting factor-mediated contraction. These results suggest that cilostazol improves endothelial functions in OLETF mesenteric arteries by increasing EDHF signaling, and that it normalizes some metabolic abnormalities in OLETF rats. On that basis, cilostazol may prove to be a potent drug for the clinical treatment of diabetic vasculopathy.
糖尿病会损害内皮功能，这种效应可被视为糖尿病患者心血管疾病发展的一个标志。西洛他唑是一种选择性磷酸二酯酶3抑制剂，目前用于治疗糖尿病血管并发症患者。然而，西洛他唑对内皮源性舒张因子[特别是一氧化氮（NO）和超极化因子（EDHF）]介导的反应以及收缩因子的影响仍不清楚。在此，我们假设西洛他唑可以改善从2型糖尿病大冢长-埃文斯-德岛肥胖（OLETF）大鼠分离的肠系膜动脉中的内皮功能障碍。使用经西洛他唑治疗（100 mg/kg/天，持续4周）或未治疗的OLETF大鼠和对照（大冢长-埃文斯-德岛大鼠），我们检测了乙酰胆碱诱导的内皮依赖性反应以及细胞通透性环磷酸腺苷（cAMP）类似物诱导的肠系膜上动脉舒张。我们还测定了这些动物的血液参数。在OLETF大鼠中，西洛他唑的长期治疗降低了甘油三酯、非酯化脂肪酸和瘦素的血液水平，并提高了抗氧化能力，但未改变血糖或胰岛素水平。在对经西洛他唑治疗的OLETF动物的肠系膜动脉进行的研究中，西洛他唑治疗改善了：（a）乙酰胆碱诱导的EDHF介导的舒张和（b）cAMP介导的舒张。然而，西洛他唑并未改变NO介导的舒张或内皮源性收缩因子介导的收缩。这些结果表明，西洛他唑通过增加EDHF信号传导来改善OLETF肠系膜动脉的内皮功能，并且它使OLETF大鼠的一些代谢异常恢复正常。在此基础上，西洛他唑可能被证明是一种治疗糖尿病血管病变的有效药物。
