Fenofibrate, an Anti-Dyslipidemia Drug, Elicits the Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and AMP-Activated Protein Kinase
Fenofibrate, an Anti-Dyslipidemia Drug, Elicits the Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and AMP-Activated Protein Kinase
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DOI：
10.1167/iovs.11-8841
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发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Yoshida, Akitoshi
中科院分区：
文献类型：
--
作者：
Omae, Tsuneaki;Nagaoka, Taiji;Yoshida, Akitoshi
目的.虽然最近的临床试验表明，非诺贝特是有效的治疗糖尿病视网膜病变，这种有益的作用机制仍然不清楚。在本研究中，我们研究了非诺贝特对猪视网膜小动脉血管扩张作用的影响。分离猪视网膜小动脉（内径60-90 μ m），插管，加压（55 cmH（2）O），体外无血流。视频显微镜技术记录的直径反应非诺贝特。视网膜小动脉对非诺贝特（10 nM至30 μ M）的反应呈剂量依赖性扩张。这种血管舒张作用在去除内皮后显著降低。N ω-硝基-L-精氨酸甲酯（一氧化氮[NO]合成酶抑制剂）、1H-（1，2，4）恶二唑（4，3-α）喹喔啉-1-酮（可溶性鸟苷酸环化酶抑制剂）、渥曼青霉素（磷脂酰肌醇[PI] 3-激酶抑制剂）和化合物C（AMP活化蛋白激酶抑制剂）可将非诺贝特诱导的血管舒张效应减弱至与剥脱产生的效应相当的程度。GW 6471（一种过氧化物酶体增殖物激活受体-α阻断剂）预处理对非诺贝特诱导的血管舒张无显著抑制作用。非诺贝特主要引起视网膜小动脉内皮依赖性扩张。目前的研究结果表明，非诺贝特诱导的内皮依赖性血管舒张是通过释放NO介导的，NO可能通过鸟苷酸环化酶、PI 3-激酶通路和AMP-活化蛋白激酶通路的激活介导血管舒张。了解非诺贝特对视网膜微血管的舒张作用可能会改善糖尿病视网膜病变的潜在治疗。（Invest Ophthalmol维斯科学。2012; 53：2880-2886）DOI：10.1167/iovs.11-8841
PURPOSE. Although recent clinical trials have demonstrated that fenofibrate is effective for treating diabetic retinopathy, the mechanism of this beneficial effect remains unclear. In the current study, we examined the effect of the vasomotor action of fenofibrate on porcine retinal arterioles.METHODS. Porcine retinal arterioles (internal diameter, 60-90 mu m) were isolated, cannulated, and pressurized (55 cmH(2)O) without flow in vitro. Video-microscopic techniques recorded the diameter responses to fenofibrate.RESULTS. The retinal arterioles dilated in a dose-dependent manner in response to fenofibrate (10 nM to 30 mu M). This vasodilation significantly decreased after the endothelium was removed. N omega-nitro-L-arginine methyl ester (a nitric oxide [NO] synthase inhibitor), 1H-(1,2,4) oxadiazole(4,3-alpha) quinoxaline-1-one (a soluble guanylyl cyclase inhibitor), wortmannin (a phosphatidylinositol [PI] 3-kinase inhibitor), and compound C (an AMP-activated protein kinase inhibitor) attenuated the effect of fenofibrate-induced vasodilation to an extent comparable to that produced by denudation. Pretreatment with GW6471, a peroxisome proliferator-activated receptor-a blocker, did not significantly inhibit fenofibrate-induced vasodilation.CONCLUSIONS. Fenofibrate primarily elicited endothelium-dependent dilation of the retinal arterioles. The current findings suggested that fenofibrate-induced endothelium-dependent vasodilation is mediated by the release of NO, which probably mediates dilation via activation of guanylyl cyclase, the PI3-kinase pathway, and the AMP-activated protein kinase pathway. Understanding the vasodilatory effect of fenofibrate on the retinal microvasculature may improve potential therapy for diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2012; 53: 2880-2886) DOI: 10.1167/iovs.11-8841