SMA-copolymer conjugate of AHPP: A polymeric inhibitor of xanthine oxidase with potential antihypertensive effect
SMA-copolymer conjugate of AHPP: A polymeric inhibitor of xanthine oxidase with potential antihypertensive effect
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DOI：
10.1016/j.jconrel.2009.01.006
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发表时间：
2009-05-05
影响因子：
10.8
通讯作者：
Maeda, Hiroshi
中科院分区：
文献类型：
--
作者：
Fang, Jun;Iyer, Arun K.;Maeda, Hiroshi
在血管系统中，已知由黄嘌呤氧化酶（XO）产生的超氧阴离子（O-2(-)）通过与一氧化氮（NO）反应并消耗一氧化氮（NO）来调节血管张力，从而决定血管舒张。我们之前报道了一种有效的XO抑制剂，4-氨基-6-羟基吡唑嘧啶（AHPP）的显著降压作用。然而，AHPP不溶于水，这阻碍了其在体内的应用。因此，本研究采用苯乙烯-马来酸共聚物（SMA, SMA-AHPP）制备了一种水溶性AHPP聚合物共轭物。SMA-AHPP对XO的抑制活性（K-i = 0.25 μ M）与天然AHPP （K-i = 0.17 μ M）相当，同时具有良好的水溶性，现在可以全身注射。采用自发性高血压大鼠（SHR）进行体内实验，分别静脉注射（15、30 mg/kg）和口服（100 mg/kg） SMA-AHPP的降压作用。结果显示，SHR大鼠血压显著降低（高达30%）；这种降压作用在服用SMA-AHPP后至少持续24小时。这些发现强烈表明SMA-AHPP作为一种具有持续体内活性的抗高血压药物的潜在价值，值得进一步研究。(c) 2009 Elsevier B.V.版权所有
In vascular system, superoxide anion (O-2(-)) generated by xanthine oxidase (XO) is known to regulate vascular tonus by reacting with, and thus consuming nitric oxide (NO), which determines vasorelaxation. We previously reported the remarkable antihypertensive effect of a potent XO inhibitor, 4-amino -6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP). However, AHPP is insoluble in water, which hamper its in vivo application. Therefore, in this study we prepared a water soluble polymeric conjugate of AHPP, by using a styrene maleic acid copolymer (SMA, SMA-AHPP). SMA-AHPP showed similar inhibitory activity against XO (K-i = 0.25 mu M) comparable to native AHPP (K-i = 0.17 mu M), while exhibiting good water-solubility, which now made it possible for systemic injection. In vivo experiments were carried out to examine the anti hypertensive effect of SMA-AHPP using the spontaneously hypertensive rats (SHR) by i.v. injection (15, 30 mg/kg) or by oral administration (100 mg/kg) of SMA-AHPP. The results showed significantly reduced blood pressures (up to 30% reduction) of SHR rats; this anti hypertensive effect continued for at least 24 h after SMA-AHPP administration. These findings strongly suggest the potential value of SMA-AHPP as an anti hypertensive agent with sustained in vivo activity, which warrants further investigations. (c) 2009 Elsevier B.V. All rights reserved.