Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, induces dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels.
Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, induces dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels.
复制标题
吡格列酮是一种过氧化物酶体增殖物激活受体-γ 激动剂，可诱导离体猪视网膜小动脉扩张：一氧化氮和钾通道的作用。
DOI：
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发表时间：
2011
影响因子：
4.4
通讯作者：
A. Yoshida
中科院分区：
文献类型：
--
作者：
Tsuneaki Omae;T. Nagaoka;Ichiro Tanano;A. Yoshida
目的
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动脉粥样硬化保护作用，可降低糖尿病患者的心血管风险。检查了吡格列酮对视网膜微血管直径的影响，并确定该影响是否依赖于平滑肌中的内皮和/或钾通道，以揭示参与该血管活性的信号传导机制。
方法
分离猪视网膜小动脉，插管，并在体外加压而不流动。视频显微镜技术记录了对吡格列酮的直径反应。
结果
视网膜小动脉对吡格列酮的反应呈浓度依赖性（10 nM-10 μM）扩张，去除内皮后缩小60%。一氧化氮（NO）合酶抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）抑制吡格列酮诱导的血管舒张，与剥脱相当。可溶性鸟苷酸环化酶（1H-1，2，4-恶二唑并[4，3-a]喹喔啉-1-酮）的抑制、磷脂酰肌醇（PI）3-激酶（渥曼青霉素）的阻断以及化合物C（AMP活化蛋白激酶（AMPK）抑制剂）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（+）通道阻滞剂四乙铵和电压门控K（+）（Kv）抑制剂4-氨基吡啶（4-AP）抑制。用GW 9662（一种PPAR-γ拮抗剂）进行腔内和腔外给药，同样可抑制吡格列酮诱导的血管舒张。L-NAME和4-AP联合给药几乎消除了吡格列酮诱导的血管舒张。
结论
吡格列酮分别抑制NO释放和Kv通道激活介导的视网膜小动脉内皮依赖性和非依赖性扩张。NO介导的扩张途径可能通过鸟苷酸环化酶、PI 3-激酶/Akt和AMPK信号转导的激活而发生。了解吡格列酮对视网膜血管的影响可能为治疗糖尿病视网膜病变的治疗进展提供新的见解。
PURPOSE
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.
METHODS
Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to pioglitazone.
RESULTS
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.
CONCLUSIONS
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.
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影响因子：
20.1
作者：
Marx, N;Schönbeck, U;Plutzky, J
通讯作者：
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10.1152/ajpheart.01052.2002
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2000-01-01
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