Soluble epoxide hydrolase inhibition in hypertensive rats improves hippocampal parenchymal arteriole structure and ion channel function

Vascular contributions to cognitive impairment and dementia (VCID) is the second most common dementia subtype behind Alzheimer's disease (AD). Mid-life hypertension, a leading risk factor for VCID, damages cerebral arteries and contributes to vascular insufficiency. This form of hypertension is more common in males; however, it disproportionately increases the risk of dementia when it occurs in premenopausal females. Soluble epoxide hydrolase (sEH) is a potential therapeutic target for VCID. sEH metabolizes EETs, which are potent vasodilators derived from arachidonic acid. Using a hypertensive model of VCID, we showed that chronic sEH inhibition enhances cerebral perfusion in males, but not females, and improves memory function in both sexes. Perfusion is regulated by artery structure and vasodilation; thus, we hypothesized that in stroke-prone spontaneously hypertensive rats (SHRSP), pharmacological inhibition of sEH with trifluoromethoxyphenyl-3 (1-propionylpiperidin-4-yl) urea (TPPU) restores HPA endothelial function and reverses inward remodeling of hippocampal parenchymal arterioles (HPA). 20-week-old SHRSP were treated with vehicle or TPPU (3mg/kg/day) for 8 weeks. HPA endothelial function and structure were assessed by pressure myography. Data are presented as means ± SEM. TPPU treatment increased maximum dilation produced in response to small- and intermediate-Ca 2+ -activated K+ channel (IKCa/SKCa) activation using the non-specific agonist, NS309 (10-5M) (32.5%±6.3 vs. 61.1%±4.0, male vehicle vs. male TPPU, p=0.03; 32.7%±9.2 vs. 69.7%±6.0, female vehicle vs. female TPPU, p=0.04; n=6-8). IKCa- and SKCa- specific antagonists, TRAM-34 (1.0 μM) and apamin (300 nM) respectively, were used to determine the individual ion channel contributions to vasodilation. IKCa channels are the major contributor to NS309-mediated dilation in HPAs. TPPU treatment increased IKCa-mediated vasodilation in both male and female SHRSP compared to sex-matched vehicle controls (4.7%±19.0 vs. 63.8%±5.7, male vehicle vs. male TPPU, p < 0.01; 31.2%±10.2 vs. 76.7%±1.2, female vehicle vs. female TPPU, p=0.04; n=4-6). sEH inhibition did not significantly increase vasodilation in response to SKCa activation in either sex (20.9%±2.3 vs. 29.0%±5.9, male vehicle vs. male TPPU, p=0.76; 18.4%±6.2 vs. 10.1%±10.0, female vehicle vs. female TPPU, p=0.86; n=4-6). TPPU treatment reversed HPA remodeling in males, as shown by increased HPA pressure-dependent lumen area (ANOVA p< 0.01) between TPPU- and vehicle-treated SHRSP (n=9). This occurred without a decrease in wall thickness (ANOVA p=0.78). Similarly, in female SHRSP (n=10), TPPU treatment increased HPA lumen area (ANOVA p< 0.01) without changing wall thickness (ANOVA p=0.58). These results expand our understanding of the effects of hypertension and sEH inhibition on a vital yet understudied segment of the cerebral vasculature and support the therapeutic potential of targeting sEH in VCID. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.