Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Mass, USA.
Stroke. 2010 Aug;41(8):1815-9. doi: 10.1161/STROKEAHA.109.577635. Epub 2010 Jul 1.
Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGCalpha(1)(-/-)) with that in wild-type mice.
Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion.
Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGCalpha(1)(-/-) compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGCalpha(1)(-/-) mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGCalpha(1)(-/-) than in the wild-type mice.
sGCalpha(1) deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGCalpha(1)beta(1) is protective in ischemic stroke.
一氧化氮介导内皮依赖性血管舒张，调节脑血流，并决定中风的结果。一氧化氮信号部分通过刺激可溶性鸟苷酸环化酶（sGC）合成 cGMP。为了研究 sGC 在中风损伤中的作用，我们比较了缺乏 sGC 的α 1 亚单位（sGCalpha(1)(-/-)）的小鼠与野生型小鼠的大脑缺血再灌注的结果。
比较了两种小鼠基因型的血压、脑血管解剖结构和加压颈动脉的血管反应性。在大脑中动脉闭塞和再灌注之前和期间测量脑血流。然后评估了 1 小时闭塞和 23 小时再灌注后以及 24 小时闭塞后的神经功能缺损和梗死体积。
两种基因型的血压和脑血管解剖结构相似。我们发现，与野生型小鼠相比，sGCalpha(1)(-/-)小鼠对乙酰胆碱或硝普钠的颈动脉舒张反应减弱。在闭塞期间，两种基因型的脑血流缺损没有差异，但在再灌注期间，sGCalpha(1)(-/-)小鼠的脑血流减少了 45%。在两种基因型中，闭塞 24 小时后，梗死体积和神经功能缺损相似。在 1 小时缺血和 23 小时再灌注后，sGCalpha(1)(-/-)小鼠的梗死体积增加了 2 倍，神经功能缺损更严重。
sGCalpha(1)缺乏会损害血管对一氧化氮的反应性，并与不完全再灌注、更大的梗死体积和更严重的神经损伤有关，这表明 sGCalpha(1)beta(1)产生的 cGMP 在缺血性中风中具有保护作用。
