Ethyl Nitrite and Subarachnoid Hemorrhage

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DESCRIPTION (provided by applicant): Cerebral vasospasm develops following subarachnoid hemorrhage (SAH), especially in patients with aneurysm rupture and causes major neurological and cognitive deficits and death. Current therapy has had limited impact on vasospasm-induced injury and outcome. Nitric oxide (NO) is decreased after SAH, which is believed to be a major factor contributing to vasospasm. Increasing NO by treatment with NO donors or precursors has been tried for almost two decades. These agents do increase vessel diameter supporting a role of NO in the pathomechanism. However, nonselective vasodilation also results in complications (e.g., systemic hypotension and steal syndrome) that have limited clinical application. S-nitrosyl-hemoglobin (SNO-Hb) carries both O2 and NO and has the capacity of selectively releasing NO in tissue beds with low O2 tension. This may serve to provide sufficient flow to allow tissue survival and improved long-term function. This proposal is designed to translate biochemical properties of SNO-Hb into new therapy and determine if increased SNO-Hb, caused by the novel s-nitrosylating agent, ethyl nitrite, improves tissue perfusion and outcome. The specific aims include acute (72 hrs post-SAH) examination of the effect of ethyl nitrite on regional cerebral blood flow (rCBF), tissue edema, neurological function, and cerebral arterial narrowing in an established mouse SAH model which has previously led to positive clinical trials of HMG-CoA reductase inhibitors. In addition, effects of ethyl nitrite on long-term (4 weeks post-SAH) cognitive function and selective neuronal cell death will be examined. The study will use rCBF autoradiography, tissue edema wet-dry weight analysis, validated neurological function tests (e.g. motor, sensory, and reflexes), rotarod performance, learning set Morris water maze testing, ink-gelatin vascular casting and brain histopathology. To test for a dose-dependent effect, the results will be compared amongst sham mice and SAH mice treated with 0, 1, 10 or 20 ppm ethyl nitrite. We also will explore potential beneficial interactions between ethyl nitrite and simvastatin. In pilot experiments 20 ppm ethyl nitrite significantly increased SNO-Hb and reduced neurological deficit and improved SAH-induced arterial narrowing at 72 h following injury without adverse hemodynamic effects. The significance of the proposed studies is to prove that selective local arterial dilation can be achieved by increasing SNO-Hb through inhalation of ethyl nitrite and that NO can modulate development of SAH induced cerebral vasospasm. This translational research will significantly contribute to improved public health. This proposal is designed to examine if administration of ethyl nitrite, an s-nitrosylating agent selectively releasing nitric oxide in hypoxic area, can ameliorate subarachnoid hemorrhage induced cerebral vasospasm, subsequent cerebral blood flow reduction and tissue edema, as well as neurological and cognitive functional deficits.