Pluta Ryszar M, Oldfield Edward H
Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Rev Recent Clin Trials. 2007 Jan;2(1):59-67. doi: 10.2174/157488707779318062.
Nitric oxide (NO) is produced by the endothelial NOS (eNOS) in the intima and by the neuronal NOS (nNOS) in the adventitia of cerebral vessels. By activating soluble guanylyl cyclase, NO increases the production of 3'-5'cGMP, which relaxes smooth muscle cells and dilates the arteries in response to shear stress, metabolic demands and changes of pCO(2) (chemoregulation). 3'-5'cGMP is then metabolized by phosphodiesterases (PDEs). Aneurysmal subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow (CBF). Oxyhemoglobin, gradually released from the subarachnoid clot enveloping the conductive arteries, scavenges NO and destroys nNOS-containing neurons. This deprives the arteries of NO, leading to vasoconstriction which initiates delayed vasospasm. This arterial narrowing increases shear stress and stimulates eNOS, which under normal conditions would lead to increased production of NO and dilation of arteries. However, this does not occur because of transient eNOS dysfunction evoked by increased levels of an endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). Increased ADMA levels result from decreased elimination due to inhibition of the ADMA-hydrolyzing enzyme (DDAH 2) in arteries in spasm by hemoglobin metabolites, bilirubin-oxidized fragments (BOXes). This eNOS dysfunction sustains vasospasm until ADMA levels decrease and NO release from endothelial cells increases. This NO-based pathophysiological mechanism of vasospasm suggests that exogenous delivery of NO, modification of PDE activity, inhibition of the L-arginine-methylating enzyme (I PRMT 3) or stimulation of DDAH 2 may provide new therapies to prevent and treat vasospasm. This paper summarizes experimental and early clinical data that are consistent with the involvement of NO in delayed cerebral vasospasm after SAH and which suggests new therapeutic possibilities.
一氧化氮（NO）由脑血管内膜中的内皮型一氧化氮合酶（eNOS）及外膜中的神经元型一氧化氮合酶（nNOS）产生。通过激活可溶性鸟苷酸环化酶，NO增加3'-5'环磷酸鸟苷（cGMP）的生成，cGMP可使平滑肌细胞舒张，并使动脉在切应力、代谢需求及二氧化碳分压（pCO₂）变化（化学调节）时发生扩张。3'-5'cGMP随后被磷酸二酯酶（PDEs）代谢。动脉瘤性蛛网膜下腔出血（SAH）会中断这种脑血流（CBF）调节。从包裹传导动脉的蛛网膜下腔血凝块中逐渐释放的氧合血红蛋白会清除NO并破坏含nNOS的神经元。这使动脉失去NO，导致血管收缩，引发迟发性血管痉挛。这种动脉狭窄会增加切应力并刺激eNOS，在正常情况下这会导致NO生成增加及动脉扩张。然而，由于内源性一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）水平升高引发的短暂性eNOS功能障碍，这种情况并未发生。血红蛋白代谢产物胆红素氧化片段（BOXes）抑制痉挛动脉中的ADMA水解酶（DDAH Ⅱ），导致ADMA清除减少，使其水平升高。这种eNOS功能障碍会持续血管痉挛，直至ADMA水平降低且内皮细胞释放的NO增加。这种基于NO的血管痉挛病理生理机制表明，外源性给予NO、改变PDE活性、抑制L-精氨酸甲基化酶（I PRMT 3）或刺激DDAH Ⅱ可能为预防和治疗血管痉挛提供新的疗法。本文总结了与NO参与SAH后迟发性脑血管痉挛相关的实验及早期临床数据，并提示了新的治疗可能性。
