Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02115, USA.
BMC Pharmacol Toxicol. 2020 Feb 21;21(1):13. doi: 10.1186/s40360-020-0394-7.
Although recent studies using experimental models of ischemic brain injury indicate that systemically-administered β-blockers have potential protective effects on the cerebrovascular system, the precise mechanisms remain unclear. In addition to their cardiovascular effects, water-soluble β-blockers can pass the blood-brain barrier and may exert their vascular action on cerebral microvessels. The aim of this study was to investigate the direct effects of β-blockade on the cerebral microvasculature both in the normal state and ischemia/reperfusion state using the cranial window method.
The closed cranial window method was used to visualize the cerebral microcirculation and changes in the pial arteriole diameter in adult male rabbits. In the first experiment, various concentrations of the selective β-blocker landiolol were administered into the cranial window to evaluate the dose-response. In the second experiment, the effect of β-blockade on the brain during ischemic/reperfusion injury was investigated. Global brain ischemia/reperfusion was induced by clamping the brachiocephalic, left common carotid, and left subclavian arteries for 15 min. Either landiolol or artificial cerebrospinal fluid was infused 5 min after initiation of ischemia through 120 min after reperfusion. Pial arteriole diameter and hemodynamic and physiological parameters were recorded before ischemia, during ischemia, and 5, 10, 20, 40, 60, 80, 100, and 120 min after reperfusion.
In the first experiment, topical administration of landiolol at higher concentrations produced slight pial arteriole dilation (10 mol/L: 4.3 ± 3.4%, 10 mol/L: 8.0 ± 5.8%, 10 mol/L: 7.3 ± 4.0%). In the second experiment, the topical administration of landiolol significantly dilated the pial arteriole diameters during ischemia/reperfusion injury (ischemia: 30.6 ± 38.6%, 5 min: 47.3 ± 42.2%, 10 min: 47.8 ± 34.2%, 20 min: 38.0 ± 39.0%). There were no statistical differences in hemodynamic and physiological parameters between the landiolol and control groups.
The blockade of β-adrenergic receptors induced significant vasodilation of pial arterioles during ischemia/reperfusion injury. By contrast, only a slight dilation of the arterioles was observed in the normal state, indicating that ischemic cerebral microvessels are more susceptible to the vasodilatory effect induced by selective blockade of β-adrenergic receptors than normal microvessels.
尽管最近使用缺血性脑损伤的实验模型进行的研究表明，全身给予β受体阻滞剂对脑血管系统具有潜在的保护作用，但确切的机制仍不清楚。除了其心血管作用外，水溶性β受体阻滞剂还可以穿过血脑屏障，并可能对脑微血管发挥其血管作用。本研究旨在使用颅窗方法研究β受体阻滞剂对正常状态和缺血/再灌注状态下脑微血管的直接作用。
使用闭合颅窗方法观察成年雄性兔的脑微循环和软脑膜小动脉直径的变化。在第一个实验中，将各种浓度的选择性β受体阻滞剂拉地洛尔注入颅窗，以评估剂量反应。在第二个实验中，研究了β受体阻滞剂对缺血/再灌注损伤期间大脑的影响。通过夹闭头臂干、左颈总动脉和左锁骨下动脉 15 分钟来诱导全脑缺血/再灌注。在缺血开始后 5 分钟至再灌注后 120 分钟内，通过 120 分钟输注拉地洛尔或人工脑脊液。在缺血前、缺血期间以及再灌注后 5、10、20、40、60、80、100 和 120 分钟记录软脑膜小动脉直径和血流动力学及生理参数。
在第一个实验中，较高浓度的局部给予拉地洛尔可引起软脑膜小动脉轻微扩张（10mol/L：4.3±3.4%，10mol/L：8.0±5.8%，10mol/L：7.3±4.0%）。在第二个实验中，在缺血/再灌注损伤期间，局部给予拉地洛尔可显著扩张软脑膜小动脉直径（缺血：30.6±38.6%，5 分钟：47.3±42.2%，10 分钟：47.8±34.2%，20 分钟：38.0±39.0%）。拉地洛尔组和对照组之间的血流动力学和生理参数无统计学差异。
β肾上腺素能受体阻断诱导缺血/再灌注损伤期间软脑膜小动脉明显扩张。相比之下，在正常状态下仅观察到小动脉轻微扩张，这表明与正常微血管相比，缺血性脑微血管对选择性β肾上腺素能受体阻断引起的血管舒张作用更敏感。
