Villalba Nuria, Sonkusare Swapnil K, Longden Thomas A, Tran Tram L, Sackheim Adrian M, Nelson Mark T, Wellman George C, Freeman Kalev
From the Departments of Pharmacology, University of Vermont, Burlington, VT
J Am Heart Assoc. 2014 Dec;3(6):e001474. doi: 10.1161/JAHA.114.001474.
Traumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI.
Cerebral arteries were isolated from rats 24 hours after moderate fluid‐percussion TBI. Pressure‐induced increases in vasoconstriction (myogenic tone) and smooth muscle Ca2+ were severely blunted in cerebral arteries after TBI. However, myogenic tone and smooth muscle Ca2+ were restored by inhibition of NO synthesis or endothelium removal, suggesting that TBI increased endothelial NO levels. Live native cell NO, indexed by 4,5‐diaminofluorescein (DAF‐2 DA) fluorescence, was increased in endothelium and smooth muscle of cerebral arteries after TBI. Clamped concentrations of 20 to 30 nmol/L NO were required to simulate the loss of myogenic tone and increased (DAF‐2T) fluorescence observed following TBI. In comparison, basal NO in control arteries was estimated as 0.4 nmol/L. Consistent with TBI causing enhanced NO‐mediated vasodilation, inhibitors of guanylyl cyclase, protein kinase G, and large‐conductance Ca2+‐activated potassium (BK) channel restored function of arteries from animals with TBI. Expression of the inducible isoform of NO synthase was upregulated in cerebral arteries isolated from animals with TBI, and the inducible isoform of NO synthase inhibitor 1400W restored myogenic responses following TBI.
The mechanism of profound cerebral artery vasodilation after TBI is a gain of function in vascular NO production by 60‐fold over controls, resulting from upregulation of the inducible isoform of NO synthase in the endothelium.
据报道，创伤性脑损伤（TBI）会增加大脑中一氧化氮（NO）的浓度，并可能导致脑血管张力丧失；然而，过量NO对脑血管系统的来源、数量及后果尚不清楚。我们的目的是阐明TBI后脑动脉张力降低的机制。
在中度液体冲击性TBI后24小时从大鼠分离脑动脉。TBI后脑动脉中压力诱导的血管收缩增加（肌源性张力）和平滑肌Ca2+严重减弱。然而，通过抑制NO合成或去除内皮可恢复肌源性张力和平滑肌Ca2+，这表明TBI增加了内皮NO水平。以4,5-二氨基荧光素（DAF-2 DA）荧光为指标的活原生细胞NO在TBI后脑动脉的内皮和平滑肌中增加。需要20至30 nmol/L的钳夹NO浓度来模拟TBI后观察到的肌源性张力丧失和（DAF-2T）荧光增加。相比之下，对照动脉中的基础NO估计为0.4 nmol/L。与TBI导致NO介导的血管舒张增强一致，鸟苷酸环化酶、蛋白激酶G和大电导Ca2+激活钾（BK）通道的抑制剂恢复了TBI动物动脉的功能。从TBI动物分离的脑动脉中诱导型NO合酶的表达上调，并且诱导型NO合酶抑制剂1400W恢复了TBI后的肌源性反应。
TBI后脑动脉深度血管舒张的机制是内皮中诱导型NO合酶上调导致血管NO生成功能比对照增加60倍。
