Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids (EETs), arachidonic acid metabolites produced by cytochrome 450 enzymes, into less metabolically active compounds. sEH inhibitors have been proposed to have vascular and neural protective effects in stroke models. Studies from our lab showed that bilateral carotid artery stenosis (BCAS), a physiologically relevant model of cognitive impairment, impairs endothelium dependent dilation in penetrating arterioles (PAs) from stroke prone spontaneously hypertensive rats (SHRSPs). We hypothesized that treatment of SHRSPs with BCAS with the sEH inhibitor, trifluoromethoxyphenyl-3 (1propionylpiperidin-4-yl) urea (TPPU) would alleviate cognitive dysfunction and improve endothelium dependent dilation in PAs. Data are shown as mean ± SEM, vehicle vs TPPU, and p <0.05 (an n=3 to 12 in each group). After 8 weeks of BCAS, TPPU treated rats showed improved short-term memory (novel exploration quotient, 90 minutes retention time: 0.5 ± 0.06 vs 0.6 ± 0.04), evaluated by novel object recognition test. PA reactivity and structure was assessed by pressure myography. TPPU restored endothelial function of PAs from SHRSP with BCAS, as evidenced by increased dilation to carbachol (% dilation at 10-6M: 2.7 ± 2.9 vs 16.5 ± 3.9). Inhibition of EET production with MS-PPOH (10-5M), enhanced dilation in PAs from TPPU treated SHRSP with BCAS (% dilation at 10-5M of carbachol, TPPU vs TPPU+MS-PPOH: 14.9 ± 2.9 vs 23.4 ± 3.5), while dilation in vehicle treated SHRSPs remained unaltered (% dilation at 10-5M, vehicle vs vehicle+MS-PPOH: 2.9 ± 2.9 vs -0.7 ± 5.1, p=0.96). This suggests that inhibiting EET production may unmask a compensatory dilatory mechanism in PAs from TPPU treated rats. Interestingly, PAs from TPPU treated rats were less sensitive to NO as evidenced by a reduction in the EC50 for NO- donor, sodium nitroprusside (logEC50: -7.1±0.14 vs -5.7± 0.2). This reduced sensitivity may be due to an overproduction of NO in PAs from TPPU treated rats. There was no difference in passive structure of the PAs with chronic TPPU administration. These data suggest that TPPU improves short-term memory after BCAS and this may be associated with improved endothelium-dependent dilation in the PAs.