Abstract MP56: Nitric Oxide-Therapy but Not Remote Ischemic Conditioning is Cerebroprotective in Stroke: A Study in Mouse Model of Endothelial Dysfunction and Hypertension

Abstract

Background: Remote Ischemic Conditioning (RIC) was found effective in stroke models, likely via increased endothelial nitric oxide (NO); yet RIC failed to improve clinical outcomes ( NCT02342522 ; NCT02189928 ). We anticipated that comorbidities neutralize the benefits of RIC in stroke. Hypothesis: NO-therapy but not RIC is vasculoprotective in hypertensive stroke. Methods: Aged (18±1-mo old) S100A1-hets mutant (S100A +/- ) and wild-type (WT) mice were used. As needed, mice were treated with RIC, s-nitrosoglutathione (GSNO) reductase inhibitor (GRI; 5 mg/kg nebulized once daily for 2-wks), GSNO (100-ug/kg; nebulized once daily at 2h post-TES), and/or intravenous thrombolysis (IVT; 10mg/kg at 4h post-TES). Stroke and outcome measures were performed as mentioned below. Statistical significance was determined at P &lt 0.05. Results: S100A +/- compared to WT-type mice showed significantly higher mean arterial pressure (MAP) and lower plasma-NO, supporting a hypertensive phenotype with endothelial dysfunction in S100A +/- mice. In photothrombotic stroke (PTS), RIC significantly improved cerebral blood flow (CBF), behavior and reduced infarction in WT but not in S100A +/- mice at 48h. GRI in S100A +/- mice enhanced plasma NO, improved behavior and CBF, and reduced infarction significantly as compared to vehicle-treated S100A +/- at 48h post-PTS. RIC with GRI did not produce additive protection in S100A +/- mice at 48h post-PTS, demonstrating that the preservation of NO-pool with GRI protects against stroke, but RIC is not effective to enhance this endogenous protection in hypertensive mice. Moreover, GSNO nebulization but not RIC enhanced PbtO 2 , reduced BBB-leakage and brain hemoglobin (Hb)-content at 24h after thromboembolic stroke with and without IVT. Conclusions: NO-therapies but not RIC is effective in hypertensive stroke. RIC- and NO- therapies need further validation in comorbid stroke before embarking on the clinical trial.