Abstract 5831: Soluble Guanylate Cyclase Alpha 1 Beta 1 Limits Stroke Size and Attenuates Neurological Injury in a Mouse Model of Cerebral Ischemia-reperfusion
Background: NO-signaling mediates endothelium-dependent vasodilation and cerebral blood flow (CBF) and determines the outcome of cerebral ischemia in intact animals. NO signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To understand the role of sGC in physiological outcome of stroke, we compared wild-type (WT) and mice deficient in the alpha 1 subunit of sGC (sGCα1−/−mice) at baseline and after cerebral ischemia and reperfusion (I/R).
Animals and Methods: Blood pressure, resting CBF (hydrogen clearance), morphology of the brain vasculature (carbon black injections), and vascular reactivity of pressurized carotid arteries to acetylcholine (ACh) were studied in wild-type (WT) and sGCα1−/−mice on a C57BL/6 background. For the cerebral I/R model, a filament was introduced in the middle cerebral artery and withdrawn after 1 hour. Cortical CBF (Laser Doppler) was continuously monitored. Body temperature was maintained at 36 –37°C. 24 hours after reperfusion, neurological deficit (behavioral scoring) and infarct volume (2,3,5-triphenyltetrazolium chloride staining) were determined. Statistical analysis was performed with a t-test.
Results: Blood pressure, brain vasculature and resting CBF were similar in WT and sGCα1−/− mice. Vasodilation in response to ACh was significantly lower in sGCα1−/− mice than in WT mice (EC50: 120±49 vs 24±10 nM, respectively, mean± SD, P<0.02). The cortical CBF demonstrated significantly decreased (21–30 %) reperfusion in sGCα1−/− mice as compared to WT mice. The infarct volume was larger in sGCα1−/− than in WT mice (102±35 vs 71±39 mm3, n=15 and 16, respectively; P<0.03). Neurological deficit following stroke was exacerbated in sGCα1−/− mice (3 points) as compared with WT mice (2 points). Conclusion: Impaired vascular reactivity to ACh associated with sGCα1−/− deficiency correlated with greater stroke damage in sGCα1−/− than in WT mice. Together, these findings suggest that cGMP generated by sGC protects against ischemia/reperfusion injury in mouse brain. Accordingly, compounds that can activate sGC hold great therapeutic potential in a setting of stroke.