Stroke has been the third leading cause of death for the past 3 decades in the United States. Although thrombolysis with tissue plasminogen activator is the only treatment for ischemic stroke, most patients are not candidates for receiving thrombolysis due to the risk of hemorrhage. Prevention or protection from stroke is an alternative approach to decrease the mortality rate. Animal models using spontaneously hypertensive stroke prone rats (SHR-SP) are useful in determining the effectiveness of new therapeutics. Interestingly, several studies using SHR-SP have shown that the severity of damage resulting from cerebral ischemia can be therapeutically reduced independent of blood pressure. Although mechanisms for protection independent of blood pressure control in SHR-SP rats are not clear, some possible explanations could be decreased arterial stiffness, improved vascular dilation, or suppressed inflammatory response to the ischemic tissue. A novel mediator of both vascular function and cerebrovascular blood flow is the CYP450 metabolite 11,12 epoxyeicosatrienoic acid (EET), a hyperpolarizing factor produced by the endothelium and neuronal cells important for matching cerebral blood flow to metabolic demand. EETs can be broken down by the soluble epoxide hydrolase (SEH) into a less active metabolite. EET levels can be elevated via inhibition of SEH. SEH polymorphisms in humans have been linked to ischemic stroke. We have data showing that inhibition of SEH can increase EET levels and decrease the infarct size induced by cerebral artery occlusion independent of blood pressure. In addition we have data showing SEH inhibition can decrease cerebral artery stiffness and can decrease inflammation induced renal damage. We will test the hypothesis that SEH inhibition decreases infarct size caused by cerebral ischemia independent of blood pressure control due to the ability of SEH inhibitors to decrease inflammation, improve vascular dilation, and prevent vascular fibrosis. We will measure cytokine and adhesion molecule expression in SHR-SP and Wistar Kyoto rats. We will use cerebral arteriograph preps to detect improvements in vasoreactivity. We will also determine if SEH inhibition can decrease fibrosis by using histology and zymography. Elucidating the mechanism of SEH inhibition will aid in determining its potential therapeutic use in high risk patients.
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