Abstract
Abstract only
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 < 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.