Acute eNOS inhibition did not alter early AT1 blocker treatment induced reduction of blood pressure after the induction of cerebral ischemia.

<p>A schematic diagram showing the experimental design (A). Blood pressure telemetry showing the hypotensive effect of Candesartan following cerebral ischemia. This effect was not altered with acute eNOS inhibition before the induction of cerebral ischemia. Data presented as mean±SEM; n = 5–6 animals per group.</p

A schematic representation of the main findings.

<p>Acute administration of ARBs improves short term functional outcome through an eNOS mediated amelioration of ER stress and BDNF/TrkB mediated signaling. Acute eNOS inhibition increases NOGO-A, nNOS expression and JNK phosphorylation.</p

eNOS inhibition induces the expression and activity of anti-recovery mechanisms after cerebral ischemia.

<p>Acute L-NIO treatment increased nNOS (F = 7.44, df = 3; p = 0.0014) (A) and Nogo-A expression (B) in the ipsilateral hemisphere (F = 11.68 df = 3; p<0.0001) This increase was associated with a concomitant increase in JNK phosphorylation (F = 28.46, df = 3; p<0.0001) (C). Data presented as mean±SEM. Solid columns represent ipsilateral hemisphere, columns with stripes represent contralateral hemisphere. S refers to the ipsilateral hemisphere; NS refers to the contralateral hemisphere. a, b or A, B Pairs of means with different letters are significantly different from each other. n = 6–8 animals per group.</p

eNOS inhibition alters nitrosative stress levels after stroke.

<p>Acute L-NIO treatment did not affect the nitrosative stress levels in the ipsilateral hemisphere ()(A). In contrast, L-NIO induced an increased nitrosative stress in the contralateral hemispheres of both candesartan and saline treated animals (F = 4.76, df = 3;p = 0.008)(B). a, b Pairs of means with different letters are significantly different from each other. Data presented as mean±SEM; n = 6–8 per group.</p

Early AT1 blockade ameliorates ischemia-induced increase in ER stress.

<p>Candesartan treatment at time of reperfusion reduced the expression of CHOP (F = 12.52, df = 3: p = 0.0007) (A), cleaved ATF6 (F = 7.88; df = 3; p = 0.0044) (C) and increased GRP78 expression in an eNOS dependent manner (F = 6.433, df = 3; p = 0.0089)(D). eNOS inhibition increased the expression of full length ATF6 (F = 8.264, df = 3; p = 0.0078) (B) Data presented as mean±SEM. Solid columns represent ipsilateral hemisphere, columns with stripes represent contralateral hemisphere. S refers to the ipsilateral hemisphere; NS refers to the contralateral hemisphere. a, b Pairs of means with different letters are significantly different from each other * n = 4 per group.</p

Early AT1 blockade improved 24-hour functional outcome measures while not affecting hemorrhagic transformation in hypertensive animals.

<p>Neither candesartan nor L-NIO had an effect on the development of hemorrhagic transformation (A). Candesartan improved neurological outcome after stroke, as assessed by modified Bederson, in an eNOS independent manner (B). After 7 days, there was a significant effect of time (p<0.01) in all measures of neurobehavioral outcome, demonstrating a gradual recovery from the initial deficits in all treatment groups. The candesartan-treated group (without eNOS inhibition) had better Bederson (2C) and Paw grasp (2D) scores than the other groups, but neither reached statistical significance. a, b: Pairs of means with different letters are significantly different from each other. Data presented as mean±SEM; n = 6–8 per group. Statistical analysis was done as a 2×2 factorial analysis. For clarity, animals that received saline injections before the induction of tMCAO are identified by the treatment they received after tMCAO only.</p