Endothelin receptor antagonist preserves microvascular perfusion and reduces ischemic brain damage following permanent focal ischemia

被引:59
作者
Dawson, DA
Sugano, H
McCarron, RM
Hallenbeck, JM
Spatz, M
机构
[1] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA
[2] USN, Resuscitat Med Dept, Med Res Ctr, Gaithersburg, MD 20899 USA
关键词
endothelin-1; cerebral ischemia; microvascular perfusion; ET-1 receptor antagonist; spontaneously hypertensive rat;
D O I
10.1023/A:1021139713026
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Synthesis and release of the potent vasoconstrictor peptide endothelin-1 (ET-1) increases following cerebral ischemia and has previously been shown to mediate the delayed hypoperfusion associated with transient global ischemia. In this study we assessed the impact of ET-1 on perfusion and infarct volume in a focal model of cerebral ischemia by use of the selective ETA receptor antagonist Ro 61-1790 (affinity for ETA receptor 1000 fold greater than ETB receptor). Control rats subjected to permanent middle cerebral artery occlusion (MCAO) showed extensive reductions in microvascular perfusion 4 h post-MCAO that were significantly attenuated by Ro 61-1790 pretreatment (10 mg/kg, i.v.). Ro 61-1790 concomitantly and significantly reduced the ischemic lesion volume in the same animals. This effect was maintained 24 h post-MCAO providing that the animals received additional i.v. injections of 5 mg/kg Ro 61-1790 at 5 h and 8 h after MCAO. These findings demonstrate that ETA receptor antagonism partially preserves tissue perfusion following focal ischemia and that this effect is associated with significant neuroprotection. The results also support the hypothesis that vasoactive mediators, and ET-1 in particular, are important contributors to the pathogenesis of cerebral ischemic injury.
引用
收藏
页码:1499 / 1505
页数:7
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