缺血后再灌注引起实质小动脉平滑肌钙敏化和血管收缩。
Postischemic reperfusion causes smooth muscle calcium sensitization and vasoconstriction of parenchymal arterioles.
机构信息
From the Department of Neurological Sciences (M.J.C., S.-L.C., J.S.), Department of Pharmacology (M.J.C., M.J.T., J.E.B.), and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Vermont, Burlington (M.J.C., N.G.).
出版信息
Stroke. 2014 Aug;45(8):2425-30. doi: 10.1161/STROKEAHA.114.005888. Epub 2014 Jun 26.
BACKGROUND AND PURPOSE
Parenchymal arterioles (PAs) are high-resistance vessels in the brain that connect pial vessels to the microcirculation. We previously showed that PAs have increased vasoconstriction after ischemia and reperfusion that could increase perfusion deficit. Here, we investigated underlying mechanisms by which early postischemic reperfusion causes increased vasoconstriction of PAs.
METHODS
Isolated and pressurized PAs from within the middle cerebral artery territory were studied in male Wistar rats that were either nonischemic control (n=34) or after exposure to transient middle cerebral artery occlusion (MCAO) by filament occlusion for 2 hours with 30 minutes of reperfusion (MCAO; n=38). The relationships among pressure-induced tone, smooth muscle calcium (using Fura 2), and membrane potential were determined. Sensitivity of the contractile apparatus to calcium was measured in permeabilized arterioles using Staphylococcus aureus α-toxin. Reactivity to inhibition of transient receptor potential melastanin receptor type 4 (9-phenanthrol), Rho kinase (Y27632), and protein kinase C (Gö6976) was also measured.
RESULTS
After MCAO, PAs had increased myogenic tone compared with controls (47±2% versus 35±2% at 40 mm Hg; P<0.01), without an increase in smooth muscle calcium (177±21 versus 201±16 nmol/L; P>0.05) or membrane depolarization (-38±4 versus -36±1 mV; P>0.05). In α-toxin-permeabilized vessels, MCAO caused increased sensitivity of the contractile apparatus to calcium. MCAO did not affect dilation to transient receptor potential melastanin receptor type 4 or protein kinase C inhibition but diminished dilation to Rho kinase inhibition.
CONCLUSIONS
The increased vasoconstriction of PAs during early postischemic reperfusion seems to be due to calcium sensitization of smooth muscle and could contribute to infarct expansion and limit neuroprotective agents from reaching their target tissue.
背景与目的
脑实质小动脉（PA）是连接软脑膜血管与微循环的高阻力血管。我们之前的研究表明，PA 在缺血再灌注后会出现血管收缩增强，从而导致灌注不足。在此，我们研究了早期缺血再灌注引起 PA 血管收缩增强的潜在机制。
方法
从雄性 Wistar 大鼠大脑中动脉区域分离并加压的 PA，在非缺血对照组（n=34）或用纤维蛋白栓子闭塞 2 小时并再灌注 30 分钟的短暂性大脑中动脉闭塞（MCAO；n=38）后进行研究。测定压力诱导的张力、平滑肌钙（用 Fura 2 测定）和膜电位之间的关系。用金黄色葡萄球菌α-毒素测量通透性 PA 中收缩装置对钙的敏感性。还测定了对瞬时受体电位黑素皮质素受体 4（9-菲咯啉）、Rho 激酶（Y27632）和蛋白激酶 C（Gö6976）抑制的反应性。
结果
MCAO 后，PA 的肌源性张力较对照组增加（47±2%比 40 mm Hg 时的 35±2%；P<0.01），但平滑肌钙（177±21 比 201±16 nmol/L；P>0.05）或膜去极化（-38±4 比 -36±1 mV；P>0.05）无增加。在α-毒素通透性血管中，MCAO 导致收缩装置对钙的敏感性增加。MCAO 不影响瞬时受体电位黑素皮质素受体 4 或蛋白激酶 C 抑制的扩张，但减少 Rho 激酶抑制的扩张。
结论
缺血再灌注早期 PA 的血管收缩增强似乎是由于平滑肌钙敏化所致，这可能导致梗死扩大，并限制神经保护剂到达其靶组织。
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