Nitric Oxide in Cerebral Vasospasm: Theories, Measurement, and Treatment
Figure 1
The regulation of nitric oxide after subarachnoid hemorrhage. Schematic demonstrating the production of NO from its precursors and its significance in SAH. Solid arrows depict positive regulatory steps. Dotted, gray arrows depict negative regulatory steps. (a) NO stimulation down the cGMP-mediated signaling pathway is critical for vasodilation and maintenance of cerebral blood flow. All NO donor strategies outlined in the text are intended to stimulate this final common pathway. (b) The three forms of nitric oxide synthases play critical roles in the pathogenesis of SAH and vasospasm. iNOS and eNOS activity are upregulated after SAH. Primate models suggest that nNOS levels decrease after SAH and may precipitate the development of vasospasm, potentially due to Hb-mediated oxidative damage. (c) Classical evidence suggests that NO is scavenged by the Hb that is released into the CSF after SAH-induced vascular injury, as a potential mechanism underlying vasospastic collapse. Hb also may trigger the production of the protein ADMA, an endogenous inhibitor of NOS that is hypothesized to play a major role in vasospasm. (d) NO is metabolized into nitrite (NO2) and nitrate (NO3), which serve as indirect measurements of NO in clinical and animal models. New evidence suggest that nitrite can be metabolized back into NO by hemoglobin in its deoxygenated form, leading to promising investigations regarding nitrite donors for treatment of SAH. (e) Recent investigations, based to a large extent on animal models, focus on the potential role of eNOS uncoupling in the pathogenesis of vasospasm. eNOS uncoupling occurs after SAH, through a mechanism that may stem from binding by ADMA, micronutrient deficiency, presence of superoxide, or lack of the substrate arginine. The eNOS-catalyzed formation of peroxynitrite from NO and reactive oxygen species may contribute to the development of delayed neurologic damage after SAH.
