Methotrexate and MX-68, a new derivative of methotrexate, limit infarct size via adenosine-dependent mechanisms in canine hearts
Methotrexate and MX-68, a new derivative of methotrexate, limit infarct size via adenosine-dependent mechanisms in canine hearts
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DOI：
10.1097/00005344-200404000-00013
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发表时间：
2004-04-01
影响因子：
3
通讯作者：
Kitakaze, M
中科院分区：
文献类型：
--
作者：
Asanuma, H;Sanada, S;Kitakaze, M
甲氨蝶呤是一种抗风湿剂，最近有报道称其抗炎作用是通过胞外5‘-核苷酸酶和腺苷依赖机制实现的。由于胞外-5‘核苷酸酶参与腺苷的合成，而腺苷对缺血/再灌注损伤有很强的心肌保护作用，我们研究了甲氨蝶呤或MX-68[N-1-((2，4-二氨基-6-蝶啶)甲基)-3，4-二氢-2H-1，4-苯并噻嗪-7-甲酰基]-N-2-氨基己二酸是否通过腺苷依赖机制缩小心肌梗死范围。在Beagle犬，左冠状动脉前降支通过旁路管灌流，阻断90分钟，然后再灌流6小时。TTC染色评价脑梗塞面积。MX-68组较未用药组心肌梗死面积缩小(13.7±1.9比38.6±5.3%，P<；0.01)。腺苷受体拮抗剂8-磺基茶碱(8-SPT)(8-SPT组和MX-68+8-SPT组分别为45.0+/-4.6%和46.8+/-5.8%)或胞外5‘-核苷酶抑制剂α，β-亚甲基腺苷5’-二磷酸(AMP-CP组分别为44.0+/-4.5%和46.7+/-5.8%)可完全阻断这种作用。甲氨蝶呤也将梗塞面积缩小到与MX-68组相当的水平，其作用也被8-SPT减弱。两组间侧支血流量和危险面积差异无统计学意义。我们得出结论，甲氨蝶呤及其衍生物(MX-68)均通过腺苷依赖机制限制梗塞范围。
Methotrexate, an anti-rheumatic agent, has recently been reported to show an anti-inflammatory action via ecto-5'-nucleotidase- and adenosine-dependent mechanisms. Because ecto-5'nucleotidase contributes to the production of adenosine and adenosine has a potent cardioprotective effect against ischemia/reperfusion injury, we investigated whether methotrexate or MX-68 [N-1-((2,4-diamino-6-pteridinyl) methyl)-3,4-dihydro-2H-1,4benzothiazine-7- carbonyl]-N-2- aminoadipic acid] could reduce infarct size via adenosine-dependent mechanisms. In beagle dogs, the left anterior descending coronary artery was perfused through a bypass tube, which was occluded for 90 minutes followed by 6 hours of reperfusion. The size of infarcts was assessed by TTC staining. MX-68 reduced infarct size compared with that in untreated dogs (13.7 1.9 versus 38.6 +/- 5.3%, P < 0.01). This effect was completely blunted by either the adenosine receptor antagonist 8-sulfoplienyltheophylline (8-SPT) (45.0 +/- 4.6% and 46.8 +/- 5.8% in the 8-SPT and MX-68 + 8-SPT groups, respectively) or by the ecto-5'-nucleotidase inhibitor alpha,beta-methylenadenosine 5'-diphosphate (AMP-CP) (44.0 +/- 4.5% and 46.7 +/- 5.8% in the AMP-CP and MX-68 + AMP-CP groups, respectively). Methotrexate also reduced infarct size to a level comparable with that in the MX-68 group, and its effect was also blunted by 8-SPT. There were no significant differences of collateral blood flow or risk area between the groups. We conclude that methotrexate and its derivative (MX-68) both limit infarct size via adenosine-dependent mechanisms.