Effects of S -Nitrosoglutathione on Acute Vasoconstriction and Glutamate Release After Subarachnoid Hemorrhage

Abstract

Background and Purpose-Subarachnoid hemorrhage (SAH) causes acute vasoconstriction that contributes to ischemic brain injury shortly after the initial bleed. It has been theorized that decreased availability of nitric oxide (NO) may contribute to acute vasoconstriction. Therefore we examined the effect of the NO donor N-nitroso glutathione (GSNO) on acute vasoconstriction and early ischemic glutamate release after experimental SAH. Methods-SAH was induced by the endovascular suture method in anesthetized rats. GSNO (1 mol/L/kg, nϭ31) or saline (nϭ21) was injected 5 minutes after SAH. Sham-operated rats received GSNO (1 mol/L/kg, nϭ5) 5 minutes after sham surgery. Arterial and intracranial pressures, cerebral blood flow (CBF), and extracellular glutamate release were measured serially for 60 minutes after SAH. SAH size was determined, and vascular measurements were made histologically. Results-GSNO had no effect on resting blood pressure, intracranial pressure, cerebral perfusion pressure, or CBF in sham-operated animals. However, administration of GSNO after SAH was associated with significantly increased CBF (161.6Ϯ26.6% versus saline 37. Key Words: cerebral blood flow Ⅲ glutamates Ⅲ nitric oxide Ⅲ subarachnoid hemorrhage Ⅲ vasoconstriction C erebral arteries respond to subarachnoid hemorrhage (SAH) with a biphasic contraction that begins minutes after the bleed and delayed vasospasm more than 48 hours later. 1-3 Although a great deal is known about the mechanisms and management of delayed vasospasm, less is known about the physiology, treatment, and importance of acute vasoconstriction. Different mechanisms may underlie the 2 processes, 4 and a great variety have been implicated. [5][6][7][8][9][10][11] Recently we have shown that acute vasoconstriction is associated with decreased cerebral blood flow (CBF), ischemic glutamate release, and premature mortality after experimental SAH. 12 If acute vasoconstriction could be pharmacologically attenuated, then SAH-induced brain injury could potentially be reduced.Resting cerebrovascular tone is maintained by a balance between opposing vasoconstrictive and vasodilatory forces, and both are pathologically altered in the acute phases of SAH. One of the most important of these is the resting vasodilatory influence of nitric oxide (NO). NO has been shown to induce endothelium-dependent vasodilatation via a cGMP-mediated See Editorial Comment, page 1961 mechanism. 13 Loss of endothelium-mediated vasodilatation 14,15 and decreased cGMP production 16,17 have been shown to contribute to vasospasm after SAH.Because administration of an NO donor after SAH should potentially restore c-GMP-dependent vasodilatation, a number of different NO donors have been tested for their ability to attenuate delayed vasospasm. 18 -21 Recent studies have suggested that sodium nitroprusside administered intrathecally 22 or intra-arterially 23 increases CBF acutely after SAH. In preliminary studies we have found that it also causes profound hypotension in this setting (J.B. Bederson, MD, et al, ...

Experimental Subarachnoid Hemorrhage Causes Early and Long-Lasting Microarterial Constriction and Microthrombosis: An in-vivo Microscopy Study

“…Studies using tissue penetrating twophoton microscopy will be needed to address this issue. Another limitation of the current study is that we focused our interest on the microcirculation and did not investigate large cerebral vessels, which may also show spasm early after hemorrhage in rodents (Bederson et al, 1998;Sehba et al, 1999). Therefore, we cannot realize if and how acute macrovasospasms and microvasospasms may be linked to each other.…”

“…So far, however, most of these investigations were performed on fixed tissue (Bederson et al, 1998;Sehba et al, 1999Sehba et al, , 2005Sehba et al, , 2007 or only acutely ( < 2 hours) after SAH (Sun et al, 2009). Accordingly, little is known about the long-term spatial and temporal characteristics of post hemorrhagic microvascular constriction in the in-vivo situation.…”

S-Nitrosoglutathione Reduces Inflammation and Protects Brain against Focal Cerebral Ischemia in a Rat Model of Experimental Stroke

“…It also has the ability to modulate blood vessel tone (Rodriguez et al, 2003) and blood perfusion (Kuo et al, 2004b). S-Nitrosoglutathione has been shown to reverse acute vasoconstriction and prevent ischemic brain injury after subarachnoid hemorrhage (Sehba et al, 1999). It also protects the brain from mitochondrial dysfunction (Ju et al, 2004).…”

“…Unlike other classes of NO donors, GSNO is a stable compound and does not decompose spontaneously, and requires additional agents or enzymes including GSNO reductase or thioredoxin system (Steffen et al, 2001;Zeng et al, 2001) for its metabolism. It reduces the frequency of embolic signals (Kaposzta et al, 2002a, b;Molloy et al, 1998) and can reverse acute vasoconstriction, preventing ischemic brain injury after subarachnoid hemorrhage (Sehba et al, 1999). Administration of GSNO has been shown to suppress iNOS induction and enhance eNOS expression in pedicle vessels, resulting in blood perfusion and a higher flap survival after I/R injury (Kuo et al, 2004a, b).…”

Perspectivas en el tratamiento del vasospasmo cerebral inducido por hemorragia subaracnoidea

“…Se ha comprobado que los niveles de NO disminuyen 60 minutos después de la HSA 73 . y que la administración de un "donador de NO" puede aumentar el CBF y disminuir la isquemia cerebral en la HSA 72 . Una disminución del NO por inhibición de la NOS tiene como consecuencia una reducción del CBF debido a una vasoconstricción cerebral 19 .…”