Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
Invest Ophthalmol Vis Sci. 2011 Aug 24;52(9):6749-56. doi: 10.1167/iovs.10-6826.
Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, has anti-inflammatory and atheroprotective effects on vascular tissue and may reduce cardiovascular risk in patients with diabetes. The effect of pioglitazone on the retinal microvascular diameter was examined, and it was determined whether the effect depends on the endothelium and/or potassium channels in smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity.
Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to pioglitazone.
The retinal arterioles dilated in a concentration-dependent (10 nM-10 μM) manner in response to pioglitazone and decreased by 60% after endothelium removal. The nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) inhibited pioglitazone-induced vasodilation comparable to denudation. Inhibition of soluble guanylyl cyclase (1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one), blockade of phosphatidylinositol (PI) 3-kinase (wortmannin), and pretreatment with compound C, an AMP-activated protein kinase (AMPK) inhibitor, were comparable to l-NAME. Pioglitazone-induced vasodilation also was inhibited by a nonselective K(+) channel blocker, tetraethylammonium, and a voltage-gated K(+) (Kv) inhibitor, 4-aminopyridine (4-AP). Treatment with intraluminal and extraluminal GW9662, a PPAR-γ antagonist, similarly inhibited pioglitazone-induced vasodilation. Co-administration of l-NAME and 4-AP almost eliminated pioglitazone-induced vasodilation.
Pioglitazone elicits endothelium-dependent and -independent dilation of retinal arterioles mediated by NO release and Kv channel activation, respectively. The NO-mediated dilation pathway probably occurs via activation of guanylyl cyclase, PI3-kinase/Akt, and AMPK signaling. Understanding the effect of pioglitazone on retinal vasculature may provide new insights into therapeutic advances for treating diabetic retinopathy.
吡格列酮是一种过氧化物酶体增殖物激活受体 (PPAR)-γ 激动剂，对血管组织具有抗炎和抗动脉粥样硬化作用，可能降低糖尿病患者的心血管风险。本研究旨在观察吡格列酮对视网膜微血管直径的影响，并确定其作用是否依赖于内皮细胞和/或平滑肌中的钾通道，以揭示涉及这种血管舒缩活动的信号机制。
离体培养猪视网膜小动脉，进行插管和加压，但无血流。视频显微镜技术记录了对吡格列酮的直径反应。
视网膜小动脉呈浓度依赖性（10 nM-10 μM）方式扩张，对吡格列酮的反应增加 60%，内皮细胞去除后减少。一氧化氮（NO）合酶抑制剂 N(G)-硝基-l-精氨酸甲酯（l-NAME）对吡格列酮诱导的血管舒张的抑制作用与去内皮作用相当。可溶性鸟苷酸环化酶（1H-1,2,4-恶二唑[4,3-a]喹喔啉-1-酮）的抑制剂 1H-1,2,4-恶二唑[4,3-a]喹喔啉-1-酮（1H-1,2,4-恶二唑[4,3-a]喹喔啉-1-酮）、磷脂酰肌醇（PI）3-激酶（wortmannin）的阻断以及 AMP 激活蛋白激酶（AMPK）抑制剂 Compound C 的预处理与 l-NAME 相当。吡格列酮诱导的血管舒张也被非选择性 K(+)通道阻断剂四乙铵和电压门控 K(+)（Kv）抑制剂 4-氨基吡啶（4-AP）抑制。腔内和腔外 GW9662（PPAR-γ 拮抗剂）的处理也相似地抑制了吡格列酮诱导的血管舒张。l-NAME 和 4-AP 的联合给药几乎消除了吡格列酮诱导的血管舒张。
吡格列酮引起的视网膜小动脉舒张是由内皮依赖性和非内皮依赖性的 NO 释放和 Kv 通道激活介导的。NO 介导的舒张途径可能通过激活鸟苷酸环化酶、PI3-激酶/Akt 和 AMPK 信号转导来实现。了解吡格列酮对视网膜血管的作用可能为治疗糖尿病性视网膜病变的治疗进展提供新的见解。
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